Science Translational Medicine最新文献

{"title":"Disease modification upon 2 weeks of tofacitinib treatment in a mouse model of chronic epilepsy","authors":"Olivia R. Hoffman,&nbsp;Jennifer L. Koehler,&nbsp;Jose Ezekiel Clemente Espina,&nbsp;Anna M. Patterson,&nbsp;Emily S. Gohar,&nbsp;Emanuel M. Coleman,&nbsp;Barry A. Schoenike,&nbsp;Claudia Espinosa-Garcia,&nbsp;Felipe Paredes,&nbsp;Nicholas H. Varvel,&nbsp;Raymond J. Dingledine,&nbsp;Jamie L. Maguire,&nbsp;Avtar S. Roopra","doi":"10.1126/scitranslmed.adt0527","DOIUrl":"10.1126/scitranslmed.adt0527","url":null,"abstract":"<div >All current drug treatments for epilepsy, a neurological disorder affecting more than 50 million people, merely treat symptoms, and a third of patients with epilepsy do not respond to medication. There are no disease-modifying treatments that may be administered briefly to patients to enduringly eliminate spontaneous seizures and reverse cognitive deficits. Applying network approaches to whole tissue and single-nucleus transcriptomic data collected from mouse models of temporal lobe epilepsy and publicly available transcriptomic data from human temporal lobectomy samples, we confirmed a previously described pattern of rapid and transient induction of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway within days of epileptogenic insult. This was followed by a resurgent activation of the JAK/STAT pathway weeks to months later with the onset of spontaneous seizures. Targeting the first wave of JAK/STAT activation after epileptic insult did not prevent seizures. However, inhibition of the second wave with CP690550 (tofacitinib) over a 2-week period enduringly suppressed seizures, rescued deficits in spatial memory, and alleviated epilepsy-associated histopathological alterations. Seizure suppression lasted for at least 2 months after the final dose. These results indicate that reignition of inflammatory JAK/STAT3 signaling in chronic epilepsy opens a window for disease modification with the US Food and Drug Administration–approved, orally available drug CP690550.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 790","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adt0527","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pentameric complex is not required for congenital CMV transmission in seronegative rhesus macaques","authors":"Hsuan-Yuan Wang,&nbsp;Husam Taher,&nbsp;Craig N. Kreklywich,&nbsp;Kimberli A. Schmidt,&nbsp;Elizabeth A. Scheef,&nbsp;Richard Barfield,&nbsp;Claire E. Otero,&nbsp;Sarah M. Valencia,&nbsp;Ke Zhang,&nbsp;Claire Callahan,&nbsp;Francesco Monticolo,&nbsp;Yueqing Qiao,&nbsp;Roxanne M. Gilbride,&nbsp;Chelsea M. Crooks,&nbsp;Anne Mirza,&nbsp;Kelsey Knight,&nbsp;Matilda J. Moström,&nbsp;Tabitha D. Manuel,&nbsp;Lesli Sprehe,&nbsp;Savannah Kendall,&nbsp;Nathan Vande Burgt,&nbsp;Timothy F. Kowalik,&nbsp;Peter A. Barry,&nbsp;Scott G. Hansen,&nbsp;Jian Shu,&nbsp;Alice F. Tarantal,&nbsp;Cliburn Chan,&nbsp;Daniel N. Streblow,&nbsp;Louis J. Picker,&nbsp;Amitinder Kaur,&nbsp;Klaus Früh,&nbsp;Sallie R. Permar,&nbsp;Daniel Malouli","doi":"","DOIUrl":"","url":null,"abstract":"<div >Congenital cytomegalovirus (cCMV) is the leading infectious cause of neonatal neurological impairment worldwide, but the viral factors enabling vertical spread across the placenta remain undetermined. The pentameric complex (PC), composed of the subunits gH/gL/UL128/UL130/UL131A, has been demonstrated to be important for entry into nonfibroblast cells in vitro. These findings link the PC to broad cell tropism and virus dissemination in vivo, denoting all subunits as potential targets for intervention strategies and vaccine development. To determine the relevance of the PC for congenital transmission in a translational nonhuman primate model, we engineered a rhesus CMV (RhCMV) mutant lacking the orthologs of UL128 and UL130, which demonstrated diminished infection of epithelial cells in vitro. However, intravenous inoculation of either CD4⁺ T cell–depleted or immunocompetent RhCMV-seronegative pregnant rhesus macaques (RMs) in the early second trimester with the PC-deficient mutant resulted in maternal RhCMV peak plasma viremia similar to inoculations with PC-intact RhCMV, although virus shedding in saliva and urine was limited. Infections with the PC-intact virus induced IgG responses that neutralized RhCMV entry into epithelial cells in tissue culture. These responses were reduced, but not absent, from animals infected with the PC-deficient virus, which also induced IgG responses against gH. Moreover, congenital CMV transmission was confirmed in multiple animals infected with PC-deficient virus by detecting viral DNA in the amniotic fluid, indicating that transplacental transmission in RMs is not contingent on the PC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 789","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adm8961","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterogeneous cellular responses to hyperthermia support combined intraperitoneal hyperthermic immunotherapy for ovarian cancer mouse models","authors":"Xingyuan Hu, Xiaoyan Kang, Faming Zhao, Yaoyuan Cui, Yu Fu, Xiaohang Yang, Jingjing Yin, Wenting Li, Junpeng Fan, Bin Yang, Zixuan Fang, Tianyu Qin, Xucui Zhuang, Yiting Liu, Chenzhao Feng, Yunyi Yang, Funian Lu, Li Zhang, Weihao Chen, Miaofang Wu, Ning Du, Xia Sheng, Xin Zhou, Jing Li, Gang Chen, Chaoyang Sun","doi":"10.1126/scitranslmed.adp2124","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp2124","url":null,"abstract":"The benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer remains controversial, hindering the development of rational combination therapies based on hyperthermia (HT). This study reports the preliminary results of the neoadjuvant HIPEC (NHIPEC) trial (ChiCTR2000038173), demonstrating enhanced tumor response in high-grade serous ovarian cancer with NHIPEC. Through single-cell RNA sequencing analysis, we identified both homogeneous and heterogeneous cellular responses to HT within the tumor and microenvironment. Epithelial-mesenchymal transition–activated tumor cells and matrix metallopeptidase 11 (MMP-11) <jats:sup>+</jats:sup> cancer-associated fibroblasts (CAFs) exhibited greater reductions and higher sensitivity to HT. CUT&amp;Tag and RNA sequencing integration unveiled the differential binding programs and transcriptional regulatory mechanisms of HSF1 under normothermia (NT) and HT in tumor cells and CAFs. Furthermore, HT ameliorated the immunosuppressive tumor microenvironment, and in vivo mouse models confirmed the combined antitumor effects of HT and programmed cell death ligand 1 blockade. These findings provide an innovative strategy for rational combination therapy with HT in ovarian cancer.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"14 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599164","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":"A human histidyl-tRNA synthetase splice variant therapeutic targets NRP2 to resolve lung inflammation and fibrosis","authors":"Leslie A. Nangle, Zhiwen Xu, David Siefker, Christoph Burkart, Yeeting E. Chong, Liting Zhai, Yanyan Geng, Clara Polizzi, Lauren Guy, Lisa Eide, Yao Tong, Sofia Klopp-Savino, Michaela Ferrer, Kaitlyn Rauch, Annie Wang, Kristina Hamel, Steve Crampton, Suzanne Paz, Kyle P. Chiang, Minh-Ha Do, Luke Burman, Darin Lee, Mingjie Zhang, Kathleen Ogilvie, David King, Ryan A. Adams, Paul Schimmel","doi":"10.1126/scitranslmed.adp4754","DOIUrl":"https://doi.org/10.1126/scitranslmed.adp4754","url":null,"abstract":"Interstitial lung disease (ILD) consists of a group of immune-mediated disorders that can cause inflammation and progressive fibrosis of the lungs, representing an area of unmet medical need given the lack of disease-modifying therapies and toxicities associated with current treatment options. Tissue-specific splice variants (SVs) of human aminoacyl-tRNA synthetases (aaRSs) are catalytic nulls thought to confer regulatory functions. One example from human histidyl-tRNA synthetase (HARS), termed HARS <jats:sup>WHEP</jats:sup> because the splicing event resulted in a protein encompassing the WHEP-TRS domain of HARS (a structurally conserved domain found in multiple aaRSs), is enriched in human lung and up-regulated by inflammatory cytokines in lung and immune cells. Structural analysis of HARS <jats:sup>WHEP</jats:sup> confirmed a well-organized helix-turn-helix motif. This motif bound specifically and selectively to neuropilin-2 (NRP2), a receptor expressed by myeloid cells in active sites of inflammation, to inhibit expression of proinflammatory receptors and cytokines and to down-regulate inflammatory pathways in primary human macrophages. In animal models of lung injury and ILD, including bleomycin treatment, silicosis, sarcoidosis, chronic hypersensitivity pneumonitis, systemic sclerosis, and rheumatoid arthritis–ILD, HARS <jats:sup>WHEP</jats:sup> reduced lung inflammation, immune cell infiltration, and fibrosis. In patients with sarcoidosis, efzofitimod treatment resulted in down-regulation of gene expression for inflammatory pathways in peripheral immune cells and stabilization of inflammatory biomarkers in serum after steroid tapering. We demonstrate the immunomodulatory activity of HARS <jats:sup>WHEP</jats:sup> and present preclinical data supporting ongoing clinical development of the biologic efzofitimod based on HARS <jats:sup>WHEP</jats:sup> in ILD.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"8 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599291","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":"A human histidyl-tRNA synthetase splice variant therapeutic targets NRP2 to resolve lung inflammation and fibrosis","authors":"Leslie A. Nangle,&nbsp;Zhiwen Xu,&nbsp;David Siefker,&nbsp;Christoph Burkart,&nbsp;Yeeting E. Chong,&nbsp;Liting Zhai,&nbsp;Yanyan Geng,&nbsp;Clara Polizzi,&nbsp;Lauren Guy,&nbsp;Lisa Eide,&nbsp;Yao Tong,&nbsp;Sofia Klopp-Savino,&nbsp;Michaela Ferrer,&nbsp;Kaitlyn Rauch,&nbsp;Annie Wang,&nbsp;Kristina Hamel,&nbsp;Steve Crampton,&nbsp;Suzanne Paz,&nbsp;Kyle P. Chiang,&nbsp;Minh-Ha Do,&nbsp;Luke Burman,&nbsp;Darin Lee,&nbsp;Mingjie Zhang,&nbsp;Kathleen Ogilvie,&nbsp;David King,&nbsp;Ryan A. Adams,&nbsp;Paul Schimmel","doi":"","DOIUrl":"","url":null,"abstract":"<div >Interstitial lung disease (ILD) consists of a group of immune-mediated disorders that can cause inflammation and progressive fibrosis of the lungs, representing an area of unmet medical need given the lack of disease-modifying therapies and toxicities associated with current treatment options. Tissue-specific splice variants (SVs) of human aminoacyl-tRNA synthetases (aaRSs) are catalytic nulls thought to confer regulatory functions. One example from human histidyl-tRNA synthetase (HARS), termed HARS^WHEP because the splicing event resulted in a protein encompassing the WHEP-TRS domain of HARS (a structurally conserved domain found in multiple aaRSs), is enriched in human lung and up-regulated by inflammatory cytokines in lung and immune cells. Structural analysis of HARS^WHEP confirmed a well-organized helix-turn-helix motif. This motif bound specifically and selectively to neuropilin-2 (NRP2), a receptor expressed by myeloid cells in active sites of inflammation, to inhibit expression of proinflammatory receptors and cytokines and to down-regulate inflammatory pathways in primary human macrophages. In animal models of lung injury and ILD, including bleomycin treatment, silicosis, sarcoidosis, chronic hypersensitivity pneumonitis, systemic sclerosis, and rheumatoid arthritis–ILD, HARS^WHEP reduced lung inflammation, immune cell infiltration, and fibrosis. In patients with sarcoidosis, efzofitimod treatment resulted in down-regulation of gene expression for inflammatory pathways in peripheral immune cells and stabilization of inflammatory biomarkers in serum after steroid tapering. We demonstrate the immunomodulatory activity of HARS^WHEP and present preclinical data supporting ongoing clinical development of the biologic efzofitimod based on HARS^WHEP in ILD.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 789","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602918","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":"Heterogeneous cellular responses to hyperthermia support combined intraperitoneal hyperthermic immunotherapy for ovarian cancer mouse models","authors":"Xingyuan Hu,&nbsp;Xiaoyan Kang,&nbsp;Faming Zhao,&nbsp;Yaoyuan Cui,&nbsp;Yu Fu,&nbsp;Xiaohang Yang,&nbsp;Jingjing Yin,&nbsp;Wenting Li,&nbsp;Junpeng Fan,&nbsp;Bin Yang,&nbsp;Zixuan Fang,&nbsp;Tianyu Qin,&nbsp;Xucui Zhuang,&nbsp;Yiting Liu,&nbsp;Chenzhao Feng,&nbsp;Yunyi Yang,&nbsp;Funian Lu,&nbsp;Li Zhang,&nbsp;Weihao Chen,&nbsp;Miaofang Wu,&nbsp;Ning Du,&nbsp;Xia Sheng,&nbsp;Xin Zhou,&nbsp;Jing Li,&nbsp;Gang Chen,&nbsp;Chaoyang Sun","doi":"","DOIUrl":"","url":null,"abstract":"<div >The benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer remains controversial, hindering the development of rational combination therapies based on hyperthermia (HT). This study reports the preliminary results of the neoadjuvant HIPEC (NHIPEC) trial (ChiCTR2000038173), demonstrating enhanced tumor response in high-grade serous ovarian cancer with NHIPEC. Through single-cell RNA sequencing analysis, we identified both homogeneous and heterogeneous cellular responses to HT within the tumor and microenvironment. Epithelial-mesenchymal transition–activated tumor cells and matrix metallopeptidase 11 (MMP-11)⁺ cancer-associated fibroblasts (CAFs) exhibited greater reductions and higher sensitivity to HT. CUT&amp;Tag and RNA sequencing integration unveiled the differential binding programs and transcriptional regulatory mechanisms of HSF1 under normothermia (NT) and HT in tumor cells and CAFs. Furthermore, HT ameliorated the immunosuppressive tumor microenvironment, and in vivo mouse models confirmed the combined antitumor effects of HT and programmed cell death ligand 1 blockade. These findings provide an innovative strategy for rational combination therapy with HT in ovarian cancer.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 789","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602886","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":"A humanized antibody against mucormycosis targets angioinvasion and augments the host immune response","authors":"Yiyou Gu,&nbsp;Shakti Singh,&nbsp;Abdullah Alqarihi,&nbsp;Sondus Alkhazraji,&nbsp;Teclegiorgis Gebremariam,&nbsp;Eman G. Youssef,&nbsp;Hong Liu,&nbsp;Xiaomin Fan,&nbsp;Wen-Rong Jiang,&nbsp;David Andes,&nbsp;Terrence R. Cochrane,&nbsp;Julie A. Schwartz,&nbsp;Scott G. Filler,&nbsp;Priya Uppuluri,&nbsp;Ashraf S. Ibrahim","doi":"","DOIUrl":"","url":null,"abstract":"<div >Mucormycosis is a fungal infection caused by Mucorales fungi that cause severe disease and fatality, especially in immunocompromised individuals. Although vaccines and immunotherapeutics have been successful in combating viral and bacterial infections, approved antifungal immunotherapies are yet to be realized. To address this gap, monoclonal antibodies targeting invasive fungal infections have emerged as a promising approach, particularly for immunocompromised patients who are unlikely to maximally benefit from vaccines. The Mucorales spore coat (CotH) proteins have been identified as crucial fungal invasins that bind to glucose-regulated protein 78 (GRP78) and integrins of host barrier cells. Previously, we described a murine monoclonal antibody, anti-CotH C2, which protected diabetic ketoacidosis (DKA) and neutropenic mice from mucormycosis. Here, we advanced the development of the C2 immunoglobulin G1 (IgG1) by humanizing it, establishing a stable Chinese hamster ovary cell line producing the antibody at commercial yields, and carried out optimization of the upstream and downstream manufacturing processes. The resultant humanized IgG1 (VX-01) exhibited a 10-fold increase in binding affinity to CotH proteins and conferred comparable in vitro and in vivo efficacy when compared to C2 antibody. The mechanism of protection was reliant on prevention of angioinvasion and enhancing opsonophagocytic killing. VX-01 demonstrated acceptable safety profiles with no detectable damage to host cells in vitro and weak or moderate binding to only cytoplasmic proteins in ex vivo good laboratory practice–human tissue cross-reactivity studies. Our studies warrant continued development of VX-01 as a promising adjunctive immunotherapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 789","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602912","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 pentameric complex is not required for congenital CMV transmission in seronegative rhesus macaques","authors":"Hsuan-Yuan Wang, Husam Taher, Craig N. Kreklywich, Kimberli A. Schmidt, Elizabeth A. Scheef, Richard Barfield, Claire E. Otero, Sarah M. Valencia, Ke Zhang, Claire Callahan, Francesco Monticolo, Yueqing Qiao, Roxanne M. Gilbride, Chelsea M. Crooks, Anne Mirza, Kelsey Knight, Matilda J. Moström, Tabitha D. Manuel, Lesli Sprehe, Savannah Kendall, Nathan Vande Burgt, Timothy F. Kowalik, Peter A. Barry, Scott G. Hansen, Jian Shu, Alice F. Tarantal, Cliburn Chan, Daniel N. Streblow, Louis J. Picker, Amitinder Kaur, Klaus Früh, Sallie R. Permar, Daniel Malouli","doi":"10.1126/scitranslmed.adm8961","DOIUrl":"https://doi.org/10.1126/scitranslmed.adm8961","url":null,"abstract":"Congenital cytomegalovirus (cCMV) is the leading infectious cause of neonatal neurological impairment worldwide, but the viral factors enabling vertical spread across the placenta remain undetermined. The pentameric complex (PC), composed of the subunits gH/gL/UL128/UL130/UL131A, has been demonstrated to be important for entry into nonfibroblast cells in vitro. These findings link the PC to broad cell tropism and virus dissemination in vivo, denoting all subunits as potential targets for intervention strategies and vaccine development. To determine the relevance of the PC for congenital transmission in a translational nonhuman primate model, we engineered a rhesus CMV (RhCMV) mutant lacking the orthologs of UL128 and UL130, which demonstrated diminished infection of epithelial cells in vitro. However, intravenous inoculation of either CD4 <jats:sup>+</jats:sup> T cell–depleted or immunocompetent RhCMV-seronegative pregnant rhesus macaques (RMs) in the early second trimester with the PC-deficient mutant resulted in maternal RhCMV peak plasma viremia similar to inoculations with PC-intact RhCMV, although virus shedding in saliva and urine was limited. Infections with the PC-intact virus induced IgG responses that neutralized RhCMV entry into epithelial cells in tissue culture. These responses were reduced, but not absent, from animals infected with the PC-deficient virus, which also induced IgG responses against gH. Moreover, congenital CMV transmission was confirmed in multiple animals infected with PC-deficient virus by detecting viral DNA in the amniotic fluid, indicating that transplacental transmission in RMs is not contingent on the PC.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"54 1","pages":""},"PeriodicalIF":17.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143599292","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":"Postoperative adhesions are abrogated by a sustained-release anti-JUN therapeutic in preclinical models","authors":"Deshka S. Foster,&nbsp;Jason L. Guo,&nbsp;Emily Meany,&nbsp;Charlotte E. Berry,&nbsp;Mahsa Fallah,&nbsp;Maria Korah,&nbsp;Michael Januszyk,&nbsp;Khristian Erich Bauer-Rowe,&nbsp;David M. Lopez,&nbsp;Christian M. Williams,&nbsp;Rachel Song,&nbsp;Michelle Griffin,&nbsp;Alexia Kim,&nbsp;Malini S. Chinta,&nbsp;Clement D. Marshall,&nbsp;Derrick C. Wan,&nbsp;Jeong S. Hyun,&nbsp;Gerlinde Wernig,&nbsp;Jeffrey A. Norton,&nbsp;Eric A. Appel,&nbsp;Daniel Delitto,&nbsp;Michael T. Longaker","doi":"","DOIUrl":"","url":null,"abstract":"<div >Postoperative abdominal adhesions are the leading cause of bowel obstruction and a cause of chronic pain and infertility. Adhesion formation occurs after 50 to 90% of abdominal operations and has no proven preventative or treatment strategy. Abdominal adhesions derive primarily from the visceral peritoneum and are composed of polyclonally proliferating tissue-resident fibroblasts. We have previously shown that signaling of the transcription factor JUN regulates adhesiogenesis and that a small-molecule JUN inhibitor (T-5224) decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with antiadhesion properties for intraperitoneal postoperative delivery and sustained release of a JUN inhibitor for adhesion prevention. The material properties of the T-5224–hydrogel support its use for open or minimally invasive surgical application. We found this therapeutic system to be safe, well tolerated, and efficacious in murine and porcine preclinical models. T-5224–hydrogel minimized adhesion quantity and also diminished adhesion fibrosis at an ultrastructural level. Moving toward clinical translation, we developed a large mammal adhesion model in pigs with bowel resection. Single-cell transcriptomic analysis showed that <i>JUN</i> and associated pathway signaling were diminished in adhesion-derived fibroblasts treated with T-5224–hydrogel. The JUN-inhibiting T-5224–hydrogel provided robust prevention of adhesion without deleterious effects on bowel anastomosis or abdominal wall healing. Adhesion biology is similar across surgical sites, and, therefore, this formulation has potential for applicability across the body. The development of therapeutics to prevent adhesions is of paramount importance with potential for high-impact translation to patient care to address a common, unmet clinical need.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 789","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602916","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":"Itaconate restrains acute proinflammatory activation of microglia MG after traumatic brain injury in mice","authors":"Ning Liu,&nbsp;Yinghua Jiang,&nbsp;Yuwen Xiu,&nbsp;Giovane G. Tortelote,&nbsp;Winna Xia,&nbsp;Yingjie Wang,&nbsp;Yadan Li,&nbsp;Samuel Shi,&nbsp;Jinrui Han,&nbsp;Charles Vidoudez,&nbsp;Aim Niamnud,&nbsp;Mitchell D. Kilgore,&nbsp;Di Zhou,&nbsp;Mengxuan Shi,&nbsp;Stephen A. Graziose,&nbsp;Jia Fan,&nbsp;Prasad V. G. Katakam,&nbsp;Aaron S. Dumont,&nbsp;Xiaoying Wang","doi":"","DOIUrl":"","url":null,"abstract":"<div >Traumatic brain injury (TBI) rapidly triggers proinflammatory activation of microglia, contributing to secondary brain damage post-TBI. Although the governing role of energy metabolism in shaping the inflammatory phenotype and function of immune cells has been increasingly recognized, the specific alterations in microglial bioenergetics post-TBI remain poorly understood. Itaconate, a metabolite produced by the enzyme aconitate decarboxylase 1 [IRG1; encoded by immune responsive gene 1 (<i>Irg1</i>)], is a pivotal metabolic regulator in immune cells, particularly in macrophages. Because microglia are macrophages of the brain parenchyma, the IRG1/itaconate pathway likely modulates microglial inflammatory responses. In this study, we explored the role of the IRG1/itaconate pathway in regulating microglial bioenergetics and inflammatory activation post-TBI using a mouse controlled cortical impact (CCI) model. We isolated microglia before and 4 and 12 hours after TBI and observed a swift but transient increase in glycolysis coupled with a prolonged disruption of mitochondrial metabolism after injury. Despite an up-regulation of Irg1 expression, itaconate in microglia declined after TBI. Microglia-specific <i>Irg1</i> gene knockout (<i>Irg1</i>-Mi-KO) exacerbated metabolic changes, intensified proinflammatory activation and neurodegeneration, and worsened certain long-term neurological deficits. Supplementation with 4-octyl itaconate (OI) reinstated the use and oxidative metabolism of glucose, glutamine, and fatty acid, thereby enhancing microglial bioenergetics post-TBI. OI supplementation also attenuated proinflammatory activation and neurodegeneration and improved long-term neurological outcomes. These results suggest that therapeutically targeting the itaconate pathway could improve microglial energy metabolism and neurological outcomes after TBI.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 789","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602913","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}