Science Translational Medicine最新文献

{"title":"Delayed low-dose oral administration of 4′-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease","authors":"Stephen R. Welch, Jessica R. Spengler, Jonna B. Westover, Kevin W. Bailey, Katherine A. Davies, Virginia Aida-Ficken, Gregory R. Bluemling, Kirsten M. Boardman, Samantha R. Wasson, Shuli Mao, Damien L. Kuiper, Michael W. Hager, Manohar T. Saindane, Meghan K. Andrews, Rebecca E. Krueger, Zachary M. Sticher, Kie Hoon Jung, Payel Chatterjee, Punya Shrivastava-Ranjan, Michael K. Lo, JoAnn D. Coleman-McCray, Teresa E. Sorvillo, Sarah C. Genzer, Florine E. M. Scholte, Jamie A. Kelly, M. Harley Jenks, Laura K. McMullan, César G. Albariño, Joel M. Montgomery, George R. Painter, Michael G. Natchus, Alexander A. Kolykhalov, Brian B. Gowen, Christina F. Spiropoulou, Mike Flint","doi":"10.1126/scitranslmed.ado7034","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado7034","url":null,"abstract":"Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4′-fluorouridine (4′-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4′-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4′-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4′-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4′-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4′-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"97 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678332","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":"Vagal stimulation ameliorates murine colitis by regulating SUMOylation","authors":"Ayman Youssef, Ata Ur Rehman, Mohamed Elebasy, Jatin Roper, Shehzad Z. Sheikh, Jorn Karhausen, Wei Yang, Luis Ulloa","doi":"10.1126/scitranslmed.adl2184","DOIUrl":"https://doi.org/10.1126/scitranslmed.adl2184","url":null,"abstract":"Inflammatory bowel diseases (IBDs) are chronic debilitating conditions without cure, the etiologies of which are unknown, that shorten the lifespans of 7 million patients worldwide by nearly 10%. Here, we found that decreased autonomic parasympathetic tone resulted in increased IBD susceptibility and mortality in mouse models of disease. Conversely, vagal stimulation restored neuromodulation and ameliorated colitis by inhibiting the posttranslational modification SUMOylation through a mechanism independent of the canonical interleukin-10/α7 nicotinic cholinergic vagal pathway. Colonic biopsies from patients with IBDs and mouse models showed an increase in small ubiquitin-like modifier (SUMO)2 and SUMO3 during active disease. In global genetic knockout mouse models, the deletion of <jats:italic>Sumo3</jats:italic> protected against development of colitis and delayed onset of disease, whereas deletion of <jats:italic>Sumo1</jats:italic> halted the progression of colitis. Bone marrow transplants from <jats:italic>Sumo1</jats:italic> -knockout (KO) but not <jats:italic>Sumo3</jats:italic> -KO mice into wild-type mice conferred protection against development of colitis. Electric stimulation of the cervical vagus nerve before the induction of colitis inhibited SUMOylation and delayed the onset of colitis in <jats:italic>Sumo1</jats:italic> -KO mice and resulted in milder symptoms in <jats:italic>Sumo3</jats:italic> -KO mice. Treatment with TAK-981, a first-in-class inhibitor of the SUMO-activating enzyme, ameliorated disease in three murine models of IBD and reduced intestinal permeability and bacterial translocation in a severe model of the disease, suggesting the potential to reduce progression to sepsis. These results reveal a pathway of vagal neuromodulation that reprograms endogenous stress-adaptive responses through inhibition of SUMOylation and suggest SUMOylation as a therapeutic target for IBD.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"6 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678953","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":"Disrupting the RNA polymerase II transcription cycle through CDK7 inhibition ameliorates inflammatory arthritis","authors":"Xi Chen, Gayathri Shibu, Baila A. Sokolsky, Tamar Nicole Soussana, Logan Fisher, Dinesh K. Deochand, Marija Dacic, Ian Mantel, Daniel C. Ramirez, Richard D. Bell, Tinghu Zhang, Laura T. Donlin, Susan M. Goodman, Nathanael S. Gray, Yurii Chinenov, Robert P. Fisher, Inez Rogatsky","doi":"10.1126/scitranslmed.adq5091","DOIUrl":"https://doi.org/10.1126/scitranslmed.adq5091","url":null,"abstract":"Macrophages are key drivers of inflammation and tissue damage in autoimmune diseases including rheumatoid arthritis. The rate-limiting step for transcription of more than 70% of inducible genes in macrophages is RNA polymerase II (Pol II) promoter-proximal pause release; however, the specific role of Pol II early elongation control in inflammation, and whether it can be modulated therapeutically, is unknown. Genetic ablation of a pause-stabilizing negative elongation factor (NELF) in macrophages did not affect baseline Pol II occupancy but enhanced the transcriptional response of paused anti-inflammatory genes to lipopolysaccharide followed by secondary attenuation of inflammatory signaling in vitro and in the K/BxN serum transfer mouse model of arthritis. To pharmacologically disrupt the Pol II transcription cycle, we used two covalent inhibitors of the transcription factor II H-associated cyclin-dependent kinase 7 (CDK7), THZ1 and YKL-5-124. Both reduced Pol II pausing in murine and human macrophages, broadly suppressed induction of pro- but not anti-inflammatory genes, and rapidly reversed preestablished inflammatory macrophage polarization. In mice, CDK7 inhibition ameliorated both acute and chronic progressive inflammatory arthritis. Lastly, CDK7 inhibition down-regulated a pathogenic gene expression signature in synovial explants from patients with rheumatoid arthritis. We propose that interfering with Pol II early elongation by targeting CDK7 represents a therapeutic opportunity for rheumatoid arthritis and other inflammatory diseases.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"38 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678330","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":"NIT2 dampens BRD1 phase separation and restrains oxidative phosphorylation to enhance chemosensitivity in gastric cancer","authors":"Ziyang Wang, Yuqin Di, Xiangqiong Wen, Ye Liu, Lvlan Ye, Xiang Zhang, Jiale Qin, Youpeng Wang, Huiying Chu, Guohui Li, Weijing Zhang, Xiongjun Wang, Weiling He","doi":"10.1126/scitranslmed.ado8333","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado8333","url":null,"abstract":"5-Fluorouracil (5-FU) chemoresistance contributes to poor therapeutic response and prognosis of gastric cancer (GC), for which effective strategies to overcome chemoresistance are limited. Here, using a CRISPR-Cas9 system, we identified that nitrilase family member 2 (NIT2) reverses chemoresistance independent of its metabolic function. Depletion or low expression of NIT2 led to 5-FU resistance in GC cell lines, patient-derived organoids, and xenografted tumors. Mechanistically, NIT2 interacted with bromodomain-containing protein 1 (BRD1) to inhibit HBO1-mediated acetylation of histone H3 at lysine-14 (H3K14ac) and RELA-targeted oxidative phosphorylation (OXPHOS) gene expression. Upon 5-FU stimulation, NIT2 phosphorylation by Src at Y49 promoted the dissociation of NIT2 from BRD1, followed by binding to E3 ligase CCNB1IP1, causing autophagic degradation of NIT2. Consequently, reduced NIT2 protein resulted in BRD1 forming phase separation and binding to histone H3, as well as increased RELA stability due to suppression of inhibitor of growth family member 4–mediated RELA ubiquitination. In addition, NIT2 expression negatively correlated with H3K14ac and OXPHOS and positively correlated with the chemotherapeutic responses and prognosis of patients with GC. Our findings reveal the moonlighting function of NIT2 in chemoresistance and underscore that OXPHOS blockade by metformin enhances 5-FU chemosensitivity upon NIT2 loss.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"1 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678331","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":"Genipin rescues developmental and degenerative defects in familial dysautonomia models and accelerates axon regeneration","authors":"Kenyi Saito-Diaz, Paula Dietrich, Tripti Saini, Md Mamunur Rashid, Hsueh-Fu Wu, Mohamed Ishan, Xin Sun, Sydney Bedillion, Archie Jayesh Patel, Anthony Robert Prudden, Camryn Gale Wzientek, Trinity Nora Knight, Ya-Wen Chen, Geert-Jan Boons, Shuibing Chen, Lorenz Studer, Michael Tiemeyer, Bingqian Xu, Ioannis Dragatsis, Hong-Xiang Liu, Nadja Zeltner","doi":"10.1126/scitranslmed.adq2418","DOIUrl":"https://doi.org/10.1126/scitranslmed.adq2418","url":null,"abstract":"The peripheral nervous system (PNS) is essential for proper body function. A high percentage of the world’s population suffers from nerve degeneration or peripheral nerve damage. Despite this, there are major gaps in the knowledge of human PNS development and degeneration; therefore, there are no available treatments. Familial dysautonomia (FD) is a devastating disorder caused by a homozygous point mutation in the gene <jats:italic>ELP1</jats:italic> . FD specifically affects the development and causes degeneration of the PNS. We previously used patient-derived induced pluripotent stem cells (iPSCs) to show that peripheral sensory neurons (SNs) recapitulate the developmental and neurodegenerative defects observed in FD. Here, we conducted a chemical screen to identify compounds that rescue the SN differentiation inefficiency in FD. We identified that genipin restores neural crest and SN development in patient-derived iPSCs and in two mouse models of FD. Additionally, genipin prevented FD degeneration in SNs derived from patients with FD, suggesting that it could be used to ameliorate neurodegeneration. Moreover, genipin cross-linked the extracellular matrix (ECM), increased the stiffness of the ECM, reorganized the actin cytoskeleton, and promoted transcription of yes-associated protein–dependent genes. Last, genipin enhanced axon regeneration in healthy sensory and sympathetic neurons (part of the PNS) and in prefrontal cortical neurons (part of the central nervous system) in in vitro axotomy models. Our results suggest that genipin has the potential to treat FD-related neurodevelopmental and neurodegenerative phenotypes and to enhance neuronal regeneration of healthy neurons after injury. Moreover, this suggests that the ECM can be targeted to treat FD.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"253 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678955","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":"Monoclonal antibodies that block Roundabout 1 and 2 signaling target pathological ocular neovascularization through myeloid cells","authors":"Luiz Henrique Geraldo, Yunling Xu, Gaspard Mouthon, Jessica Furtado, Felipe Saceanu Leser, Levi L. Blazer, Jarrett J. Adams, Sophia Zhang, Lana Zheng, Eric Song, Mark E. Robinson, Jean-Leon Thomas, Sachdev S. Sidhu, Anne Eichmann","doi":"10.1126/scitranslmed.adn8388","DOIUrl":"https://doi.org/10.1126/scitranslmed.adn8388","url":null,"abstract":"Roundabout (ROBO) 1 and 2 are transmembrane receptors that bind secreted SLIT ligands through their extracellular domains (ECDs) and signal through their cytoplasmic domains to modulate the cytoskeleton and regulate cell migration, adhesion, and proliferation. SLIT-ROBO signaling regulates pathological ocular neovascularization, which is a major cause of vision loss worldwide, but pharmacological tools to prevent SLIT-ROBO signaling are lacking. Here, we developed human monoclonal antibodies (mAbs) against the ROBO1 and ROBO2 ECDs. One antibody that inhibited in vitro SLIT2 signaling through ROBO1 and ROBO2 (anti-ROBO1/2) also reduced ocular neovascularization in oxygen-induced retinopathy (OIR) and laser-induced corneal neovascularization (CNV) mouse models in vivo. Single-cell RNA sequencing of OIR retinas revealed that antibody treatment affected several cell types relevant to physiological and pathological angiogenesis, including endothelial cells, pericytes, and a heterogeneous population of myeloid cells. mAb treatment improved blood-retina barrier integrity and prevented pathological pericyte activation in OIR. SLIT-ROBO signaling inhibition prevented pathological activation of myeloid cells and increased neuroprotective myeloid populations normally seen in the developing retina. Microglia/infiltrating macrophage–specific ablation of <jats:italic>Robo1</jats:italic> and <jats:italic>Robo2</jats:italic> or knockout of the downstream effector phosphatidylinositol 3-kinase ( <jats:italic>Pik3cg</jats:italic> ) encoding PI3Kγ in both OIR and CNV models phenocopied anti-ROBO1/2 treatment, further demonstrating the key role of myeloid cells as drivers of ocular neovascular diseases. ROBO1/2 blocking antibodies may thus provide a promising strategy to combat inflammation in blinding eye diseases.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"6 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679131","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":"Animal models of Long Covid: A hit-and-run disease","authors":"Alexandra Schäfer, Sarah R. Leist, John M. Powers, Ralph S. Baric","doi":"10.1126/scitranslmed.ado2104","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado2104","url":null,"abstract":"The severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) pandemic has caused more than 7 million deaths globally. Despite the presence of infection- and vaccine-induced immunity, SARS-CoV-2 infections remain a major global health concern because of the emergence of SARS-CoV-2 variants that can cause severe acute coronavirus disease 2019 (COVID-19) or enhance Long Covid disease phenotypes. About 5 to 10% of SARS-CoV-2–infected individuals develop Long Covid, which, similar to acute COVID 19, often affects the lung. However, Long Covid can also affect other peripheral organs, especially the brain. The causal relationships between acute disease phenotypes, long-term symptoms, and involvement of multiple organ systems remain elusive, and animal model systems mimicking both acute and post-acute phases are imperative. Here, we review the current state of Long Covid animal models, including current and possible future applications.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"2 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601971","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":"Infection-associated chronic conditions: Why Long Covid is our best chance to untangle Osler’s web","authors":"Michael J. Peluso, Maureen R. Hanson, Steven G. Deeks","doi":"10.1126/scitranslmed.ado2101","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado2101","url":null,"abstract":"The recognition of Long Covid has renewed efforts to understand other infection-associated chronic conditions (IACCs). Here, we describe how studies of Long Covid and other IACCs might inform one another. We argue for the importance of a coordinated research agenda addressing these debilitating illnesses.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"6 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601972","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":"Symptoms after Lyme disease: What’s past is prologue","authors":"Adriana Marques","doi":"10.1126/scitranslmed.ado2103","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado2103","url":null,"abstract":"Protracted fatigue and other symptoms can occur after Lyme disease and other infections, with numerous possible drivers. Studies on posttreatment Lyme disease have been inconclusive, with no confirmed biomarker emerging. Prolonged antibiotic therapy provides no benefit. Thus, a holistic approach toward understanding and treating this complex disease is necessary.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"189 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601976","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":"Translating insights into therapies for Long Covid","authors":"Annukka A. R. Antar, Andrea L. Cox","doi":"10.1126/scitranslmed.ado2106","DOIUrl":"https://doi.org/10.1126/scitranslmed.ado2106","url":null,"abstract":"Long Covid is defined by a wide range of symptoms that persist after the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Commonly reported symptoms include fatigue, weakness, postexertional malaise, and cognitive dysfunction, with many other symptoms reported. Symptom range, duration, and severity are highly variable and partially overlap with symptoms of myalgic encephalomyelitis/chronic fatigue syndrome and other post-acute infectious syndromes, highlighting opportunities to define shared mechanisms of pathogenesis. Potential mechanisms of Long Covid are diverse, including persistence of viral reservoirs, dysregulated immune responses, direct viral damage of tissues targeted by SARS-CoV-2, inflammation driven by reactivation of latent viral infections, vascular endothelium activation or dysfunction, and subsequent thromboinflammation, autoimmunity, metabolic derangements, microglial activation, and microbiota dysbiosis. The heterogeneity of symptoms and baseline characteristics of people with Long Covid, as well as the varying states of immunity and therapies given at the time of acute infection, have made etiologies of Long Covid difficult to determine. Here, we examine progress on preclinical models for Long Covid and review progress being made in clinical trials, highlighting the need for large human studies and further development of models to better understand Long Covid. Such studies will inform clinical trials that will define treatments to benefit those living with this condition.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"35 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601975","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}