JCI insightPub Date : 2025-04-24eCollection Date: 2025-06-09DOI: 10.1172/jci.insight.187683
Margaret S Bohm, Sydney C Joseph, Laura M Sipe, Minjeong Kim, Cameron T Leathem, Tahliyah S Mims, Nathaniel B Willis, Ubaid A Tanveer, Joel H Elasy, Emily W Grey, Madeline E Pye, Zeid T Mustafa, Barbara Anne Harper, Logan G McGrath, Deidre Daria, Brenda Landvoigt Schmitt, Jelissa A Myers, Patricia Pantoja Newman, Brandt D Pence, Marie Van der Merwe, Matthew J Davis, Joseph F Pierre, Liza Makowski
{"title":"The gut microbiome enhances breast cancer immunotherapy following bariatric surgery.","authors":"Margaret S Bohm, Sydney C Joseph, Laura M Sipe, Minjeong Kim, Cameron T Leathem, Tahliyah S Mims, Nathaniel B Willis, Ubaid A Tanveer, Joel H Elasy, Emily W Grey, Madeline E Pye, Zeid T Mustafa, Barbara Anne Harper, Logan G McGrath, Deidre Daria, Brenda Landvoigt Schmitt, Jelissa A Myers, Patricia Pantoja Newman, Brandt D Pence, Marie Van der Merwe, Matthew J Davis, Joseph F Pierre, Liza Makowski","doi":"10.1172/jci.insight.187683","DOIUrl":"10.1172/jci.insight.187683","url":null,"abstract":"<p><p>Bariatric surgery is associated with improved breast cancer (BC) outcomes, including greater immunotherapy effectiveness in a preclinical BC model. A potential mechanism of bariatric surgery-associated protection is the gut microbiota. Here, we demonstrate the dependency of improved immunotherapy response on the post-bariatric surgery gut microbiome via fecal microbiota transplantation (FMT). Response to αPD-1 immunotherapy was significantly improved following FMT from formerly obese bariatric surgery-treated mice. When stool from post-bariatric surgery patients was transplanted into recipient mice and compared to the patients' presurgery transplants, postsurgery microbes significantly reduced tumor burden and doubled immunotherapy effectiveness. Microbes impact tumor burden through microbially derived metabolites, including branched-chain amino acids (BCAAs). Circulating BCAAs correlated significantly with natural killer T (NKT) cell content in the tumor microenvironment in donor mice after bariatric surgery and FMT recipients of donor cecal content after bariatric surgery compared with obese controls. BCAA supplementation replicated improved αPD-1 effectiveness in 2 BC models, supporting the role of BCAAs in increased immunotherapy effectiveness after bariatric surgery. Ex vivo exposure increased primary NKT cell expression of antitumor cytokines, demonstrating direct activation of NKT cells by BCAAs. Together, the findings suggest that reinvigorating antitumor immunity may depend on bariatric surgery-associated microbially derived metabolites, namely BCAAs.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967648","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":"Virus-induced RGMa expression drives neurodegeneration in HTLV-1-associated myelopathy.","authors":"Natsumi Araya, Makoto Yamagishi, Makoto Nakashima, Naomi Asahara, Kazuhiro Kiyohara, Satoko Aratani, Naoko Yagishita, Erika Horibe, Izumi Ishizaki, Toshiki Watanabe, Tomoo Sato, Kaoru Uchimaru, Yoshihisa Yamano","doi":"10.1172/jci.insight.184530","DOIUrl":"10.1172/jci.insight.184530","url":null,"abstract":"<p><p>Human T-lymphotropic virus type 1-associated (HTLV-1-associated) myelopathy (HAM, also known as tropical spastic paraparesis) is a rare neurodegenerative disease with largely elusive molecular mechanisms, impeding targeted therapeutic advancements. This study aimed to identify the critical molecule responsible for neuronal damage in HAM, its source, and the regulatory mechanisms controlling its expression. Utilizing patient-derived cells and established cell lines, we discovered that HTLV-1 Tax, in conjunction with specificity protein 1 (Sp1), enhanced the expression of repulsive guidance molecule A (RGMa), a protein known to contribute to neuronal damage. RGMa expression was specifically upregulated in HTLV-1-infected cells from patients with HAM, particularly in those expressing HTLV-1 Tax. Furthermore, in CD4+ cells from patients with HAM, the level of H3K27me3 methylation upstream of the RGMA gene locus was reduced, making RGMA more prone to constitutive expression. We demonstrated that HTLV-1-infected cells in HAM inflict neuronal damage via RGMa. Crucially, the neutralizing antibody against RGMa, unasnemab (MT-3921), effectively mitigated this damage in a dose-responsive manner, highlighting RGMa's pivotal role in neuronal damage and its potential as a therapeutic target for alleviating neuronal damage in HAM.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967721","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 : 2025-04-24eCollection Date: 2025-06-09DOI: 10.1172/jci.insight.188414
Charles Rabolli, Jacob Z Longenecker, Isabel S Naarmann-de Vries, Joan Serrano, Jennifer M Petrosino, George A Kyriazis, Christoph Dieterich, Federica Accornero
{"title":"The cardiac METTL3/m6A pathway regulates the systemic response to Western diet.","authors":"Charles Rabolli, Jacob Z Longenecker, Isabel S Naarmann-de Vries, Joan Serrano, Jennifer M Petrosino, George A Kyriazis, Christoph Dieterich, Federica Accornero","doi":"10.1172/jci.insight.188414","DOIUrl":"10.1172/jci.insight.188414","url":null,"abstract":"<p><p>Regulation of organismal homeostasis in response to nutrient availability is a vital physiological process that involves interorgan communication. The role of the heart in controlling systemic metabolic health is not clear. Adopting a mouse model of diet-induced obesity, we found that the landscape of N6-methyladenosine (m6A) on cardiac mRNA was altered following high-fat/high-carbohydrate feeding (Western diet). m6A is a critical posttranscriptional regulator of gene expression, the formation of which is catalyzed by methyltransferase-like 3 (METTL3). Through parallel unbiased approaches of Nanopore sequencing, mass spectrometry, and protein array, we found regulation of circulating factors under the control of METTL3. Mice with cardiomyocyte-specific deletion of METTL3 showed a systemic inability to respond to nutritional challenge, thereby mitigating the detrimental effects of Western diet. Conversely, increasing cardiac METTL3 level exacerbated diet-induced body weight gain, adiposity, and glucose intolerance. Our findings position the heart at the center of systemic metabolism regulation and highlight an m6A-dependent pathway to be exploited for the battle against obesity.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005739","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.190740
Andy Kwan Pui Chan, Liting Liu, William R Morgenlander, Manjusha Thakar, Nadine A Peart Akindele, Jacqueline Brockhurst, Shristi Ghimire, Maggie L Bartlett, Kelly A Metcalf Pate, Victor C Chu, Meghan S Vermillion, Danielle P Porter, Tomas Cihlar, Michael J Mina, H Benjamin Larman, Diane E Griffin
{"title":"Remdesivir postexposure prophylaxis limits measles-induced \"immune amnesia\" and measles antibody responses in macaques.","authors":"Andy Kwan Pui Chan, Liting Liu, William R Morgenlander, Manjusha Thakar, Nadine A Peart Akindele, Jacqueline Brockhurst, Shristi Ghimire, Maggie L Bartlett, Kelly A Metcalf Pate, Victor C Chu, Meghan S Vermillion, Danielle P Porter, Tomas Cihlar, Michael J Mina, H Benjamin Larman, Diane E Griffin","doi":"10.1172/jci.insight.190740","DOIUrl":"10.1172/jci.insight.190740","url":null,"abstract":"<p><p>Measles remains one of the most important causes of worldwide morbidity and mortality in children. Measles virus (MeV) replicates extensively in lymphoid tissue, and most deaths are due to other infectious diseases associated with MeV-induced loss of circulating antibodies to other pathogens. To determine whether remdesivir, a broad-spectrum direct-acting antiviral, affects MeV-induced loss of antibody to other pathogens, we expanded the VirScan technology to detect antibodies to both human and macaque pathogens. We measured the antibody reactivity to MeV and non-MeV viral peptides using plasma from MeV-infected macaques that received remdesivir either as postexposure prophylaxis (PEP) (d3-d14) or as late treatment (LT) (d11-d22) in comparison with macaques that were not treated. Remdesivir PEP, but not LT, limited the loss of antibody to non-MeV pathogens. Remdesivir PEP also limited the antibody response to MeV with a decrease in both the magnitude and breadth of the epitopes recognized. LT had little effect on the magnitude of the MeV-specific antibody response but affected the breadth of the response. Therefore, early, but not late, treatment of measles with the direct-acting antiviral remdesivir prevents the loss of antibody to other pathogens but decreases the response to MeV.</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":"143997123","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.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}
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