JCI insightPub Date : 2025-04-22DOI: 10.1172/jci.insight.186505
Long Wu, Allison Kensiski, Samuel J Gavzy, Hnin Wai Lwin, Yang Song, Michael T France, Ram Lakhan, Dejun Kong, Lushen Li, Vikas Saxena, Wenji Piao, Marina W Shirkey, Valeria R Mas, Bing Ma, Jonathan S Bromberg
{"title":"Rapamycin immunomodulation utilizes time-dependent alterations of lymph node architecture, leukocyte trafficking, and gut microbiome.","authors":"Long Wu, Allison Kensiski, Samuel J Gavzy, Hnin Wai Lwin, Yang Song, Michael T France, Ram Lakhan, Dejun Kong, Lushen Li, Vikas Saxena, Wenji Piao, Marina W Shirkey, Valeria R Mas, Bing Ma, Jonathan S Bromberg","doi":"10.1172/jci.insight.186505","DOIUrl":"https://doi.org/10.1172/jci.insight.186505","url":null,"abstract":"<p><p>Transplant recipients require lifelong, multimodal immunosuppression to prevent rejection by reducing alloreactive immunity. Rapamycin is known to modulate adaptive and innate immunity, but its full mechanism remains incompletely understood. We investigated the understudied effects of rapamycin on lymph node (LN) architecture, leukocyte trafficking, and gut microbiome and metabolism after 3 (early), 7 (intermediate), and 30 (late) days of rapamycin treatment. Rapamycin significantly reduced CD4+ T cells, CD8+ T cells, and Tregs in peripheral LNs, mesenteric LNs, and spleen. Rapamycin induced early proinflammation transition to protolerogenic status by modulating the LN laminin α4/α5 expression ratios (La4/La5) through LN stromal cells, laminin α5 expression, and adjustment of Treg numbers and distribution. Additionally, rapamycin shifted the Bacteroides/Firmicutes ratio and increased amino acid bioavailability in the gut lumen. These effects were evident by 7 days and became most pronounced by 30 days in naive mice, with changes as early as 3 days in allogeneic splenocyte-stimulated mice. These findings reveal what we believe to be a novel mechanism of rapamycin action through time-dependent modulation of LN architecture and gut microbiome, which orchestrates changes in immune cell trafficking, providing a framework for understanding and optimizing immunosuppressive therapies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 8","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019024","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}
JCI insightPub Date : 2025-04-22DOI: 10.1172/jci.insight.184544
Lara Henze, Nico Will, Dakyung Lee, Victor Haas, Christian Casar, Jasper Meyer, Stephanie Stein, Franziska Mangler, Silja Steinmann, Tobias Poch, Jenny Krause, Johannes Fuss, Johanna Schröder, Alexandra E Kulle, Paul-Martin Holterhus, Stefan Bonn, Marcus Altfeld, Samuel Huber, Ansgar W Lohse, Dorothee Schwinge, Christoph Schramm
{"title":"Testosterone affects female CD4+ T cells in healthy individuals and autoimmune liver diseases.","authors":"Lara Henze, Nico Will, Dakyung Lee, Victor Haas, Christian Casar, Jasper Meyer, Stephanie Stein, Franziska Mangler, Silja Steinmann, Tobias Poch, Jenny Krause, Johannes Fuss, Johanna Schröder, Alexandra E Kulle, Paul-Martin Holterhus, Stefan Bonn, Marcus Altfeld, Samuel Huber, Ansgar W Lohse, Dorothee Schwinge, Christoph Schramm","doi":"10.1172/jci.insight.184544","DOIUrl":"https://doi.org/10.1172/jci.insight.184544","url":null,"abstract":"<p><p>Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are autoimmune liver diseases with strong female predominance. They are caused by T cell-mediated injury of hepatic parenchymal cells, but the mechanisms underlying this sex bias are unknown. Here, we investigated whether testosterone contributes to T cell activation in women with PBC. Compared with sex- and age-matched healthy controls (n = 23), cisgender (cis) women with PBC (n = 24) demonstrated decreased testosterone serum levels and proinflammatory CD4+ T cell profile in peripheral blood. Testosterone suppressed the expression of TNF and IFN-γ by human CD4+ T cells in vitro. In trans men receiving gender-affirming hormone therapy (GAHT) (n = 25), testosterone affected CD4+ T cell function by inhibiting Th1 and Th17 differentiation and by supporting the differentiation into regulatory Treg. Mechanistically, we provide evidence for a direct effect of testosterone on T cells using mice with T cell-specific deletion of the cytosolic androgen receptor. Supporting a role for testosterone in autoimmune liver disease, we observed an improved disease course and profound changes in T cell states in a trans man with AIH/primary sclerosing cholangitis (PSC) variant syndrome receiving GAHT. We here report a direct effect of testosterone on CD4+ T cells that may contribute to future personalized treatment strategies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 8","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063399","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}
JCI insightPub Date : 2025-04-22DOI: 10.1172/jci.insight.189732
Valentina Vozella, Vittoria Borgonetti, Bryan Cruz, Celsey M St Onge, Ryan Bullard, Roman Vlkolinsky, Diego Gomez Ceballos, Angela R Ozburn, Amanda J Roberts, Roberto Ciccocioppo, Michal Bajo, Marisa Roberto
{"title":"Apremilast reduces co-occurring alcohol drinking and mechanical allodynia and regulates central amygdala GABAergic transmission.","authors":"Valentina Vozella, Vittoria Borgonetti, Bryan Cruz, Celsey M St Onge, Ryan Bullard, Roman Vlkolinsky, Diego Gomez Ceballos, Angela R Ozburn, Amanda J Roberts, Roberto Ciccocioppo, Michal Bajo, Marisa Roberto","doi":"10.1172/jci.insight.189732","DOIUrl":"https://doi.org/10.1172/jci.insight.189732","url":null,"abstract":"<p><p>The FDA-approved phosphodiesterase type 4 (PDE4) inhibitor, apremilast, has been recently investigated as a pharmacotherapy for alcohol use disorder (AUD) with promising efficacy in rodent models and humans. However, apremilast's effects on mechanical allodynia associated with AUD as well as distinct responses of this drug between males and females are understudied. The present study examined the behavioral and electrophysiological effects of apremilast in Marchigian Sardinian alcohol-preferring (msP) rats and their Wistar counterparts. We used a 2-bottle choice (2-BC) alcohol drinking procedure and tested mechanical sensitivity across our drinking regimen. Spontaneous inhibitory GABA-mediated postsynaptic currents from the central nucleus of the amygdala (CeA) following apremilast application were tested in a subset of rats using ex vivo electrophysiology. Transcript levels for Pde4a or -4b subtypes were assessed for their modulation by alcohol. Apremilast reduced alcohol drinking in both strains of rats. Apremilast reduced mechanical allodynia immediately after drinking, persisting into early and late abstinence. Apremilast increased GABAergic transmission in CeA slices of alcohol-exposed Wistars but not msP rats, suggesting neuroadaptations in msPs by excessive drinking and mechanical allodynia. Pde4 subtype transcript levels were increased in CeA by alcohol. These results suggest that apremilast alleviates co-occurring excessive drinking and pain sensitivity, and they further confirm PDE4's role in pain-associated AUD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 8","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984080","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}
JCI insightPub Date : 2025-04-22eCollection Date: 2025-06-09DOI: 10.1172/jci.insight.181096
Alenka Djarmila Behsen, Esten Nymoen Vandsemb, Tobias Schmidt Slørdahl, Karen Dybkær, Maja Zimmer Jakobsen, Muhammad Kashif, Johan Lund, Vincent Luong, Astrid Marta Olsnes, Anders Waage, Anne Marit Sponaas, Kristine Misund
{"title":"T cell phenotype and clonality changes in myeloma patients with short overall survival.","authors":"Alenka Djarmila Behsen, Esten Nymoen Vandsemb, Tobias Schmidt Slørdahl, Karen Dybkær, Maja Zimmer Jakobsen, Muhammad Kashif, Johan Lund, Vincent Luong, Astrid Marta Olsnes, Anders Waage, Anne Marit Sponaas, Kristine Misund","doi":"10.1172/jci.insight.181096","DOIUrl":"10.1172/jci.insight.181096","url":null,"abstract":"<p><p>Overall survival (OS) in multiple myeloma (MM) varies between a couple of months to more than 20 years, influenced by tumor characteristics, the tumor microenvironment (TME), and patient factors such as age and frailty. We analyzed sequential BM samples from 45 MM patients with OS less than 3 years versus more than 8 years using mass cytometry and bulk TCRβ sequencing. Patients with long OS demonstrated stability in the TME and T cell environments, while those with short OS had significant changes at relapse, including fewer T cells, increased Tregs, and more activated and exhausted CD8+ T cells. Notably, higher programmed cell death 1 expression in CD8+ T cells at diagnosis correlated with short OS. Additionally, short-OS patients exhibited a more monoclonal T cell environment at relapse, with abundance of hyperexpanded clones. These findings reveal distinct immune cell differences between patients with short and long OS.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144019335","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}
JCI insightPub Date : 2025-04-22DOI: 10.1172/jci.insight.178754
Ziyi Zhang, Wenyue W Ye, Anthony L Piro, Dian-Shi Wang, Ashley Untereiner, Sulayman A Lyons, Alpana Bhattacharjee, Ishnoor Singh, Jacqueline L Beaudry, Beverley A Orser, Feihan F Dai, Michael B Wheeler
{"title":"Glycine receptor activation promotes pancreatic islet cell proliferation via the PI3K/mTORC1/p70S6K pathway.","authors":"Ziyi Zhang, Wenyue W Ye, Anthony L Piro, Dian-Shi Wang, Ashley Untereiner, Sulayman A Lyons, Alpana Bhattacharjee, Ishnoor Singh, Jacqueline L Beaudry, Beverley A Orser, Feihan F Dai, Michael B Wheeler","doi":"10.1172/jci.insight.178754","DOIUrl":"https://doi.org/10.1172/jci.insight.178754","url":null,"abstract":"<p><p>Glycine and β-alanine activate glycine receptors (GlyRs), with glycine known to enhance insulin secretion from pancreatic islet β cells, primarily through GlyR activation. However, the effects of GlyR activation on β cell proliferation have not been examined. Here, we aim to investigate the potential proliferative effects of glycine and β-alanine on islets. In vitro experiments on mouse and human islets revealed that glycine and β-alanine, via GlyR activation, stimulated the proliferation of β cells and α cells, without affecting insulin or glucagon secretion. Further analysis indicated the involvement of the PI3K/mTORC1/p70S6K signaling pathway in this process. Inhibition of GlyRs and PI3K/mTORC1/p70S6K signaling attenuated proliferative effects of glycine and β-alanine. In vivo and ex vivo studies supported these findings, showing increased β and α cell mass after 12 weeks of oral administration of glycine and β-alanine, with no changes in insulin secretion or glucose homeostasis under normal conditions. However, during an acute insulin resistance induced by insulin receptor antagonist S961, glycine and β-alanine enhanced insulin secretion and reduced blood glucose levels by increasing β cell secretory capacity. These findings demonstrate glycine and β-alanine in vivo and in vitro promote islet cell proliferation via GlyR activation and the PI3K/mTORC1/p70S6K pathway, potentially providing a target to enhance islet capacity.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 8","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010436","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}
JCI insightPub Date : 2025-04-22DOI: 10.1172/jci.insight.186805
Adriana Gregory-Flores, Ivan Jm Bonet, Stève Desaivre, Jon D Levine, Stanton F McHardy, Harmannus C de Kraker, Nicholas A Clanton, Peter M LoCoco, Nicholas M Russell, Caleb Fleischer, Robert O Messing, Michela Marinelli
{"title":"A small molecule PKCε inhibitor reduces hyperalgesia induced by paclitaxel or opioid withdrawal.","authors":"Adriana Gregory-Flores, Ivan Jm Bonet, Stève Desaivre, Jon D Levine, Stanton F McHardy, Harmannus C de Kraker, Nicholas A Clanton, Peter M LoCoco, Nicholas M Russell, Caleb Fleischer, Robert O Messing, Michela Marinelli","doi":"10.1172/jci.insight.186805","DOIUrl":"https://doi.org/10.1172/jci.insight.186805","url":null,"abstract":"<p><p>The enzyme protein kinase C ε (PKCε) plays an important role in pain signaling and represents a promising therapeutic target for the treatment of chronic pain. We designed and generated a small molecule inhibitor of PKCε, CP612, and examined its effect in a rodent model of chemotherapy-induced neuropathic pain produced by paclitaxel, which does not respond well to current therapeutics. In addition, many patients with chronic pain use opiates, which over time can become ineffective, and attempts to discontinue them can increase pain thereby promoting sustained opioid use. Therefore, we also investigated if CP612 alters pain due to opioid withdrawal. We found that CP612 attenuated hyperalgesia produced by paclitaxel, and it both prevented and reversed hyperalgesia induced by opioid withdrawal. It was not self-administered and did not affect morphine self-administration. These findings suggest that inhibition of PKCε is an effective, nonaddictive strategy to treat chemotherapy-induced neuropathic pain, with the added benefit of preventing increases in pain that occur as opioid treatment is discontinued. This latter property could benefit individuals with chronic pain who find it difficult to discontinue opioids.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 8","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144017226","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}
JCI insightPub Date : 2025-04-22eCollection Date: 2025-06-09DOI: 10.1172/jci.insight.186747
Xin Li, Maria Rossing, Ana Moisés da Silva, Muthiah Bose, Thorkell Gudjónsson, Jan Benada, Jayashree Thatte, Jens Vilstrup Johansen, Judit Börcsök, Hanneke van der Gulden, Ji-Ying Song, Renée Menezes, Asma Tajik, Lucía Sena, Zoltan Szallasi, Morten Frödin, Jos Jonkers, Finn Cilius Nielsen, Claus Storgaard Sørensen
{"title":"G6PC3 promotes genome maintenance and is a candidate mammary tumor suppressor.","authors":"Xin Li, Maria Rossing, Ana Moisés da Silva, Muthiah Bose, Thorkell Gudjónsson, Jan Benada, Jayashree Thatte, Jens Vilstrup Johansen, Judit Börcsök, Hanneke van der Gulden, Ji-Ying Song, Renée Menezes, Asma Tajik, Lucía Sena, Zoltan Szallasi, Morten Frödin, Jos Jonkers, Finn Cilius Nielsen, Claus Storgaard Sørensen","doi":"10.1172/jci.insight.186747","DOIUrl":"10.1172/jci.insight.186747","url":null,"abstract":"<p><p>Mutations in genome maintenance factors drive sporadic and hereditary breast cancers. Here, we searched for potential drivers based on germline DNA analysis from a cohort consisting of patients with early-onset breast cancer negative for BRCA1/BRCA2 mutations. This revealed candidate genes that subsequently were subjected to RNA interference-based (RNAi-based) phenotype screens to reveal genome integrity effects. We identified several genes with functional roles in genome maintenance, including Glucose-6-Phosphatase Catalytic Subunit 3 (G6PC3), SMC4, and CCDC108. Notably, G6PC3-deficient cells exhibited increased levels of γH2AX and micronuclei formation, along with defects in homologous recombination (HR) repair. Consistent with these observations, G6PC3 was required for the efficient recruitment of BRCA1 to sites of DNA double-strand breaks (DSBs). RNA-Seq analysis revealed that G6PC3 promotes the expression of multiple homologous recombination repair genes, including BRCA1. Through CRISPR-Select functional-genetic phenotype analysis of G6PC3 germline mutations, we identified 2 germline G6PC3 variants displaying partial loss of function. Furthermore, our study demonstrated that G6pc3 deficiency accelerates mammary tumor formation induced by Trp53 loss in mice. In conclusion, our cohort-based functional analysis has unveiled genome maintenance factors and identified G6PC3 as a potential candidate tumor suppressor in breast cancer.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970021","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}
JCI insightPub Date : 2025-04-22eCollection Date: 2025-06-09DOI: 10.1172/jci.insight.188146
Julie D Pourtois, Naomi L Haddock, Aditi Gupta, Arya Khosravi, Hunter A Martinez, Amelia K Schmidt, Prema S Prakash, Ronit Jain, Piper Fleming, Tony H Chang, Carlos Milla, Patrick R Secor, Giulio A De Leo, Paul L Bollyky, Elizabeth B Burgener
{"title":"New Pseudomonas infections drive Pf phage transmission in CF airways.","authors":"Julie D Pourtois, Naomi L Haddock, Aditi Gupta, Arya Khosravi, Hunter A Martinez, Amelia K Schmidt, Prema S Prakash, Ronit Jain, Piper Fleming, Tony H Chang, Carlos Milla, Patrick R Secor, Giulio A De Leo, Paul L Bollyky, Elizabeth B Burgener","doi":"10.1172/jci.insight.188146","DOIUrl":"10.1172/jci.insight.188146","url":null,"abstract":"<p><p>Pf bacteriophages, lysogenic viruses that infect Pseudomonas aeruginosa (Pa), are implicated in the pathogenesis of chronic Pa infections; phage-infected (Pf+) strains are known to predominate in people with cystic fibrosis (pwCF) who are older and have more severe disease. However, the transmission patterns of Pf underlying the progressive dominance of Pf+ strains are unclear. In particular, it is unknown whether phage transmission commonly occurs horizontally between bacteria via viral particles within the airway or whether Pf+ bacteria are mostly acquired via de novo Pseudomonas infections. Here, we studied Pa genomic sequences from 3 patient cohorts totaling 662 clinical isolates from 105 pwCF. We identified Pf+ isolates and analyzed transmission patterns of Pf within patients between genetically similar groups of bacteria called \"clone types.\" We found that Pf was predominantly passed down vertically within Pa clone types and rarely via horizontal transfer between clone types within the airway. Conversely, we found extensive evidence of Pa de novo infection by a new, genetically distinct Pf+ Pa. Finally, we observed that clinical isolates showed reduced activity of type IV pili and reduced susceptibility to Pf in vitro. These results cast light on the transmission of virulence-associated phages in the clinical setting.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984033","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":"Reshaping the chromatin landscape in HUVECs from small-for-gestational-age newborns.","authors":"Lingling Yan, Zhimin Zhou, Shengcai Chen, Xin Feng, Junwen Mao, Fang Luo, Jianfang Zhu, Xiuying Chen, Yingying Hu, Yuan Wang, Bingbing Wu, Lizhong Du, Chunlin Wang, Liang Gong, Yanfen Zhu","doi":"10.1172/jci.insight.186812","DOIUrl":"https://doi.org/10.1172/jci.insight.186812","url":null,"abstract":"<p><p>Small for gestational age (SGA), with increased risk of adult-onset cardiovascular diseases and metabolic syndromes, is known to associate with endothelial dysfunction, but the pathogenic mechanisms remain unclear. In this study, the pathological state of human umbilical vein endothelial cells (HUVECs) from SGA individuals was characterized by presenting increased angiogenesis, migration, proliferation, and wound healing ability relative to their normal counterparts. Genome-wide mapping of transcriptomes and open chromatins unveiled global gene expression alterations and chromatin remodeling in SGA-HUVECs. Specifically, we revealed increased chromatin accessibility at active enhancers, along with dysregulation of genes associated with angiogenesis, and further identified CD44 as the key gene driving HUVECs' dysfunction by regulating pro-angiogenic genes' expression and activating phosphorylated ERK1/2 and phosphorylated endothelial NOS expression in SGA. In SGA-HUVECs, CD44 was abnormally upregulated by 3 active enhancers that displayed increased chromatin accessibility and interacted with CD44 promoter. Subsequent motif analysis uncovered activating protein-1 (AP-1) as a crucial transcription factor regulating CD44 expression by binding to CD44 promoter and associated enhancers. Enhancers CRISPR interference and AP-1 inhibition restored CD44 expression and alleviated the hyperangiogenesis of SGA-HUVECs. Together, our study provides a foundational understanding of the epigenetic alterations driving pathological angiogenesis and offers potential therapeutic insights into addressing endothelial dysfunction in SGA.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 8","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144012435","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":"SPOP mutations increase PARP inhibitor sensitivity via CK2/PIAS1/SPOP axis in prostate cancer.","authors":"Hui Zhang, Lili Kong, Jinhui Li, Zhihan Liu, Yiting Zhao, Xiuyi Lv, Liangpei Wu, Lin Chai, Hongjie You, Jiabei Jin, Xinyi Cao, Zhong Zheng, Yadong Liu, Zejun Yan, Xiaofeng Jin","doi":"10.1172/jci.insight.186871","DOIUrl":"https://doi.org/10.1172/jci.insight.186871","url":null,"abstract":"<p><p>It is well documented that impaired DNA damage repair (DDR) induces genomic instability that can efficiently increase the sensitivity of prostate cancer (PCa) cells to PARP inhibitors; however, the underlying mechanism remains elusive. Here, we found profound genomic instability in PCa cells with SPOP gene mutations and confirmed the sensitivity of SPOP-mutated PCa cells to olaparib-induced apoptosis. Mechanistically, we identified olaparib-induced CK2-mediated phosphorylation of PIAS1-S468, which in turn mediated SUMOylation of SPOP, thus promoting its E3 ligase activity in the DDR. Moreover, an abnormal CK2/PIAS1/SPOP axis due to SPOP mutations or defects in CK2-mediated phosphorylation of PIAS1, as well as SPOP inhibitor treatment, led to impaired DDR, thus increasing olaparib-induced apoptosis of PCa cells and enhancing olaparib sensitivity in animal models and patient-derived organoids. This suggested that disruption of the CK2/PIAS1/SPOP signaling axis could serve as an indicator for targeted therapy of PCa using a PARP inhibitor.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 8","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12016936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007044","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}
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