The FASEB Journal最新文献

{"title":"Mesenchymal retinoic acid signaling is required for normal diaphragm development in mice","authors":"Juan F. Garcia Rivas,&nbsp;Nicole H. M. Applin,&nbsp;Jaida F. P. Albrechtsen,&nbsp;Adibehalsadat Ghazanfari,&nbsp;Michael Doschak,&nbsp;Robin D. Clugston","doi":"10.1096/fj.202402182R","DOIUrl":"https://doi.org/10.1096/fj.202402182R","url":null,"abstract":"<p>Congenital diaphragmatic hernia (CDH) is characterized by incomplete formation of the diaphragm, causing herniation of the abdominal organs and subsequent lung hypoplasia; however, the etiology of CDH is poorly understood. The Retinoid Hypothesis posits that abnormal retinoic acid signaling leads to the formation of diaphragmatic hernias. Our goal is to better understand diaphragm development and the etiology of CDH. To achieve this goal, we first performed single-cell RNA sequencing analysis of the developing diaphragm, then generated a conditional retinoic acid receptor dominant negative knock-in to inhibit retinoic acid signaling in the mesenchyme of the developing diaphragm. Our single-cell RNA sequencing analysis revealed 10 distinct cell populations in the developing diaphragm, with mesenchymal cells being the primary expresser of CDH and retinoic acid signaling-related genes. Transgenic inhibition of mesenchymal retinoic acid signaling in the developing diaphragm caused hernias in 100% of embryos, recapitulating the hallmarks of CDH. Overall, our studies show that retinoic acid signaling in the mesenchymal component of the diaphragm is required for normal diaphragm development.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 3","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402182R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Marein alleviates the development of atherosclerosis through targeting miR-126/lipoprotein-associated phospholipase A2 axis","authors":"Lisha Zhao,&nbsp;Jie Xing,&nbsp;Yunfei Wang,&nbsp;Ling Xin,&nbsp;Xiaorong Cheng,&nbsp;Yanying Chen,&nbsp;Panpan Wang,&nbsp;Lanlan Zhang,&nbsp;Weiguo Zhao","doi":"10.1096/fj.202402378R","DOIUrl":"https://doi.org/10.1096/fj.202402378R","url":null,"abstract":"<p>As a classical precious medicine, <i>Coreopsis tinctoria</i> Nutt. (<i>C. tinctoria</i>) is widely utilized for treatment of cardiometabolic diseases, while the important compound of <i>C. tinctoria</i>, marein exhibits multiple beneficial biological effects that related to the pathophysiological processes underlying atherogenesis. Thus, the purpose of present study is to investigate the role of marein on the development of atherosclerosis. In the current study, we observed that marein exhibited anti-inflammatory response function verified by reduced mRNA and protein levels of classical M1 but enhanced alternative M2 macrophage genes. Moreover, marein dramatically attenuated macrophage-induced foam cell formation with up-regulated cholesterol efflux but down-regulated cholesterol influx-related genes expression in bone marrow-derived macrophage (BMDMs) administrated with oxidized low-density lipoprotein (Ox-LDL), observed by staining with Oil-Red O, RT-PCR, or western blot analysis. Treatment of ApoE knockout mice (ApoE^−/−) with marein at indicated time which consistently fed with high-fat diet for 12 weeks was utilized to explore the function of marein on atherogenesis in vivo. We revealed that marein-treated group alleviated atherosclerotic plaques in the entire aorta and aortic root and inhibited plaque vulnerability characterized by decreased necrotic core, reduced macrophage, and lipid accumulation, whereas increased fibrous cap, enhanced smooth muscle cell, and collagen deposition. Importantly, we noticed that miR-126 could target to lipoprotein-associated phospholipase A₂ (Lp-PLA₂), and enhanced miR-126 but reduced Lp-PLA₂ expression was responsible for the alleviated function of marein on macrophage dysfunction. Collectively, we identified that marein could be a promising drug for prevention of the development of atherosclerosis by protecting against macrophage-mediated foam cell formation and inflammation, partially through miR-126/Lp-PLA₂ dependent mechanism.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 3","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prodomain processing controls BMP-10 bioactivity and targeting to fibrillin-1 in latent conformation","authors":"Chara E. S. Spanou,&nbsp;Chengeng Yang,&nbsp;Alan R. F. Godwin,&nbsp;Stefanie Morosky,&nbsp;Arulselvi Anbalagan,&nbsp;Steffen Lütke,&nbsp;Matthias Mörgelin,&nbsp;Fady Marcous,&nbsp;Ubair Aziz,&nbsp;Alexander P. Wohl,&nbsp;Ishrat Jabeen,&nbsp;Manuel Koch,&nbsp;Thomas A. Jowitt,&nbsp;Beth L. Roman,&nbsp;Anna Tarakanova,&nbsp;Clair Baldock,&nbsp;Gerhard Sengle","doi":"10.1096/fj.202401694R","DOIUrl":"https://doi.org/10.1096/fj.202401694R","url":null,"abstract":"<p>Bone morphogenetic protein 10 (BMP-10) is crucial for endothelial cell signaling via activin receptor-like kinase 1 (ALK1), a pathway central to vascular homeostasis and angiogenesis. Dysregulated BMP-10 signaling contributes to cardiovascular diseases and cancer, highlighting the need to control ALK1-mediated endothelial responses to BMP-10 for therapeutic development. BMP-10 biosynthesis involves processing by proprotein convertases (PPCs) resulting in a non-covalently associated prodomain–growth factor (PD–GF) complex (CPLX), similar to other TGF-β superfamily ligands. However, the molecular requirements for BMP-10 bioactivity remain unclear. We investigated how PPC processing impacts BMP-10 structure, bioactivity, and its interaction with the extracellular matrix (ECM) protein fibrillin-1. Molecular dynamics simulations post-in silico cleavage of the BMP-10 dimer model as well as negative staining and transmission electron microscopy (TEM) revealed that PD processing increases BMP-10 flexibility converting it from a latent wide-angle conformation to a bioactive CPLX which can adopt a V-shape with tighter angle. Only processed BMP-10 demonstrated high potency in HUVEC and C2C12 cells and robust binding to immobilized BMP receptors. Circular dichroism and interaction studies revealed that the N-terminal region of the BMP-10 PD is rich in alpha-helical content, which is essential for efficient complexation with the BMP-10 GF. Binding studies and TEM analyses showed that only the processed BMP-10 CPLX interacts with the N-terminal region of fibrillin-1, causing a conformational change that renders it into a closed ring-shaped conformation. These findings suggest that PD processing induces specific folding events at the PD–GF interface, which is critical for BMP-10 bioactivity and its targeting to the ECM.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 3","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401694R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362719","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UBE2D3 functions in mouse oocyte meiotic maturation","authors":"Guorui Zhang,&nbsp;Na Zhang,&nbsp;Bin Zhang,&nbsp;Yilong Zhao,&nbsp;Qiang Wang,&nbsp;Longsen Han","doi":"10.1096/fj.202403033R","DOIUrl":"https://doi.org/10.1096/fj.202403033R","url":null,"abstract":"<p>Ubiquitin-mediated proteolysis plays a critical role in meiotic cell-cycle regulation and must be tightly controlled to achieve correct chromosome segregation. While the role of E2 ubiquitin-conjugating enzymes in mitosis is well-documented, their functions in oocyte meiosis remain largely unexplored. In this study, we identified UBE2D3 as the most highly expressed E2 enzyme in mouse oocytes, which is essential for proper meiotic division. UBE2D3 depletion caused (metaphase I) MI arrest and Cyclin B1 accumulation, whereas its overexpression led to reduced Cyclin B1 levels, kinetochore-microtubule (K-MT) mis-attachments, spindle assembly checkpoint (SAC) dysfunction, and increased aneuploidy. Notably, UBE2D3 upregulation in oocytes from aged mice contributed to age-related meiotic defects, which were partially reversed by UBE2D3 knockdown or Cyclin B1 overexpression. This study underscores the importance of the UBE2D3-Cyclin B1 axis in maintaining meiotic fidelity and highlights its potential as a therapeutic target for improving oocyte quality and fertility in aged females.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 3","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RETRACTION: Extracellular HSP27 Mediates Angiogenesis Through Toll-Like Receptor 3","authors":"","doi":"10.1096/fsb2.70367","DOIUrl":"https://doi.org/10.1096/fsb2.70367","url":null,"abstract":"<p><b>RETRACTION:</b> D. Thuringer, G. Jego, G. Wettstein, O. Terrier, L. Cronier, N. Yousfi, S. Hébrard, A. Bouchot, A. Hazoumé, A.-L. Joly, M. Gleave, M. Rosa-Calatrava, E. Solary, and C. Garrido, “Extracellular HSP27 Mediates Angiogenesis Through Toll-Like Receptor 3,” <i>The FASEB Journal</i> 27, no. 10 (2013): 4169-4183, https://doi.org/10.1096/fj.12-226977.</p><p>The above article, published online on 26 June 2013 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors; the journal Editor-in-Chief, Loren E. Wold; the Federation of American Societies for Experimental Biology; and Wiley Periodicals LLC. The retraction has been agreed upon following an investigation into concerns raised by a third party which revealed inappropriate image panel duplications between this (Figure 3A) and another article published previously in a different scientific context. The investigation also revealed that the western blot panels of Figure 4E were later reused in a publication of the same author group, depicting different experimental conditions. Due to the number and the level of errors identified in the published figures, the authors and the editors have lost confidence in the presented data and consider the conclusions substantially compromised.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 3","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fsb2.70367","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EXPRESSION OF CONCERN: Bcl-2 Overexpression in Human Melanoma Cells Increases Angiogenesis Through VEGF mRNA Stabilization and HIF-1-mediated Transcriptional Activity","authors":"","doi":"10.1096/fsb2.70311","DOIUrl":"https://doi.org/10.1096/fsb2.70311","url":null,"abstract":"<p><b>EXPRESSION OF CONCERN:</b> A. Iervolino, D. Trisciuoglio, D. Ribatti, A. Candiloro, A. Biroccio, G. Zupi, D. Del Bufalo, “Bcl-2 Overexpression in Human Melanoma Cells Increases Angiogenesis Through VEGF mRNA Stabilization and HIF-1-mediated Transcriptional Activity,” <i>The FASEB Journal</i> 16, no. 11 (2002): 1453-1455, https://doi.org/10.1096/fj.02-0122fje.</p><p>This Expression of Concern is for the above article, published online on July 01, 2002, in Wiley Online Library (http://onlinelibrary.wiley.com/), and has been issued by agreement between the journal Editor-in-Chief, Loren E. Wold; the Federation of American Societies for Experimental Biology; and Wiley Periodicals LLC. A third party reported concerns of duplication and manipulation in Figure 1, and splicing and duplication in Figures 2B and 5A. These concerns were confirmed by the journal and publisher. Author D. Del Bufalo responded to an inquiry by the journal on behalf of the authors, but the authors were not able to supply original data due to the length of time that has elapsed since publication. The Expression of Concern has been agreed on because the evidence of image manipulation and duplication calls into question the validity of the data in Figures 1, 2, and 5, which cannot be confirmed due to the lack of original data. Author D. Del Bufalo disagrees with the Expression of Concern. All other authors did not respond to our notice regarding the Expression of Concern.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 3","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fsb2.70311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALZ-801 prevents amyloid β-protein assembly and reduces cytotoxicity: A preclinical experimental study","authors":"Daiki Muramatsu,&nbsp;Takahiro Watanabe-Nakayama,&nbsp;Mayumi Tsuji,&nbsp;Kenichi Umeda,&nbsp;Sadao Hikishima,&nbsp;Hiroto Nakano,&nbsp;Yasuhiro Sakashita,&nbsp;Tokuhei Ikeda,&nbsp;Hiroki Konno,&nbsp;Noriyuki Kodera,&nbsp;Toshio Ando,&nbsp;Moeko Noguchi-Shinohara,&nbsp;Kenjiro Ono","doi":"10.1096/fj.202402622R","DOIUrl":"https://doi.org/10.1096/fj.202402622R","url":null,"abstract":"<p>Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, mainly characterized by amyloid β (Aβ) accumulation in the brain. Numerous new agents are currently undergoing clinical trials as disease-modifying therapies (DMTs) targeting Aβ. ALZ-801 is a promising candidate DMT for AD, with a phase 3 trial of ALZ-801 ongoing specifically for apolipoprotein E (APOE) ε4 homozygous patients with early-stage AD. This study aimed to examine the effects of ALZ-801 on Aβ assembly and explore its toxicological profile. Thioflavin T (ThT) assays and two imaging modalities—transmission electron microscopy (TEM) and high-speed atomic force microscopy (HS-AFM)—were used to evaluate ALZ-801's effects on Aβ assembly. To assess the effect of ALZ-801 on Aβ₄₂-induced cytotoxicity, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and lactate dehydrogenase (LDH) assays were performed. ThT assays revealed increased lag time and decreased fluorescence in the presence of ALZ-801, confirming inhibition of Aβ₄₂ fibril formation, as confirmed by TEM. Real-time observation using HS-AFM revealed that ALZ-801 inhibited the formation of Aβ₄₂ fibril from low-molecular-weight (LMW)-Aβ₄₂ in the presence of Aβ₄₂ seeds. HS-AFM also revealed that globular aggregates from LMW-Aβ₄₂ were significantly larger with ALZ-801, with few fibrils noted. MTT and LDH assays indicated that ALZ-801 prevented LMW-Aβ₄₂-induced cytotoxicity but did not reduce cytotoxicity induced by high-molecular-weight-Aβ₄₂. ALZ-801 can inhibit Aβ₄₂ aggregation by preventing both nucleus formation and fibril elongation, while promoting large globular oligomer formation, and can significantly reduce LMW-Aβ₄₂-induced cytotoxicity. These findings underscore the potential of ALZ-801 as an effective DMT for APOE ε4 homozygous patients with AD.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 3","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402622R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362720","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of proton sensor GPR68 suppresses endothelial dysfunction and acute lung injury caused by Staphylococcus aureus bacterial particles","authors":"Pratap Karki,&nbsp;Yunbo Ke,&nbsp;Chen-Ou Zhang,&nbsp;Kamoltip Promnares,&nbsp;Yue Li,&nbsp;Charles H. Williams,&nbsp;Charles C. Hong,&nbsp;Konstantin G. Birukov,&nbsp;Anna A. Birukova","doi":"10.1096/fj.202401947R","DOIUrl":"10.1096/fj.202401947R","url":null,"abstract":"<p>Lung bacterial infections, including hospital-acquired pneumonia, remain a serious problem for public health. Endothelial cell (EC) exposure to heat-killed <i>Staphylococcus aureus</i> (HKSA) represents a clinical scenario of high titers of killed bacterial particles present in the host after antibiotic therapy, which triggers inflammatory cascades, cytokine storms, and EC dysfunction leading to acute lung injury (ALI). GPR68 is a member of the proton-sensing G protein-coupled receptor family. Acting as a pH sensor, GPR68 becomes activated upon pH reduction and contributes to pathologic cell responses by activating ER stress and unfolded protein response. This study investigated the role of GPR68 in HKSA-induced EC dysfunction and HKSA-induced ALI. HKSA robustly increased GPR68 mRNA levels in human pulmonary EC and directly stimulated GPR68 activity. A selective GPR68 small molecule inhibitor, OGM-8345, attenuated HKSA-induced EC permeability and protected cell junction integrity. OGM-8345 inhibited HKSA-induced activation of inflammatory genes TNF-α, IL-6, IL-8, IL-1β, and CXCL5 and decreased cytokine secretion by HKSA-challenged EC. Co-treatment with the GPR68 activator Ogerin or medium acidification to pH 6.5 augmented HKSA-induced EC dysfunction, which was rescued by OGM-8345. Intratracheal HKSA injection increased vascular leak and lung inflammation in mice which were monitored by lung Evans blue extravasation, increased cell and protein count in bronchoalveolar lavage, and mRNA expression of inflammatory genes. ALI and barrier dysfunction was attenuated by OGM-8345. We show for the first time the role of GPR68 in mediating HKSA-induced lung injury and the strong potential for OGM-8345 as a therapeutic treatment of bacterial pathogen-induced ALI associated with tissue acidification.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 3","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202401947R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted inhibition of menin promotes β-catenin-mediated GLP-1 expression and improves glucose tolerance in high-fat diet-induced obese mice","authors":"Xiaoru Cao,&nbsp;Ling Yu,&nbsp;Qian Zhang,&nbsp;Zhaosi Cheng,&nbsp;Haiyue Meng,&nbsp;Chenghao Wang,&nbsp;Zhitao Guo,&nbsp;Yinghao Guo,&nbsp;Guoshun Xin,&nbsp;Yue Wang,&nbsp;Pingping Zhou,&nbsp;Yakun Luo,&nbsp;Bin Sun,&nbsp;Jian Ma","doi":"10.1096/fj.202402269RR","DOIUrl":"10.1096/fj.202402269RR","url":null,"abstract":"<p>Glucagon-like peptide-1 (GLP-1), derived from enteroendocrine cells, is a pivotal hormone crucial for blood glucose regulation. Menin, encoded by the <i>MEN1</i> gene and known for its tumor suppressor role, is abundantly expressed in the intestine. Previous research has demonstrated that acute <i>Men1</i> excision reverses preexisting glucose intolerance in high-fat diet-fed mice. However, its impact on GLP-1 expression in enteroendocrine cells has not been investigated. In the present study, both the knockdown of <i>Men1</i> and the administration of the MI-463 menin inhibitor increased GLP-1 expression in glucose-stimulated STC-1 cells. Additionally, administering MI-463 to obese mice significantly elevated GLP-1 levels in both ileal epithelial cells and serum. Mechanistically, menin inhibition enhanced the nuclear accumulation of β-catenin, allowing it to bind TCF7L2, thereby increasing glucagon gene (<i>Gcg</i>) transcription. Furthermore, compared with control mice, mice with intestinal epithelial cell-specific <i>Men1</i> knockdown exhibited significant improvements in glucose tolerance under fat challenge, which was correlated with elevated GLP-1 levels. These findings suggest that menin-mediated regulation of GLP-1 expression may be an important mechanism through which menin inhibiton alleviates type 2 diabetes.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 3","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143191177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual independent mechanisms underlying gut epithelial remodeling upon sugar substitute consumption","authors":"Dong Woo Seo,&nbsp;Kyung Tae Hong,&nbsp;Jung Hoon Lee,&nbsp;Jun-Seok Lee,&nbsp;Yong Taek Jeong","doi":"10.1096/fj.202402105RR","DOIUrl":"https://doi.org/10.1096/fj.202402105RR","url":null,"abstract":"<p>Intestinal epithelial cells (IECs) are dynamically regulated by luminal contents, including dietary ingredients, food additives, and microbiota-derived metabolites. Although sugar substitutes are commonly used as food additives for their sweet taste and lower calorie content, there is limited experimental evidence regarding their potential to drive gut remodeling. In this study, we designed experimental models for short-term consumption of erythritol, a natural sugar alcohol widely used as a sugar substitute, and investigated its effects on gut remodeling and the underlying mechanisms. Our findings indicate that erythritol consumption induces hyperplasia in tuft cells (TCs) and goblet cells (GCs), as well as enhances the activity of intestinal stem cells–increases in expression levels of <i>leucine-rich repeat containing G protein-coupled receptor 5</i> (<i>Lgr5</i>), the key intestinal stem cell marker, in the number of proliferating stem cells, and facilitation of their differentiation into villi cells–while maintaining the number of <i>Lgr5</i>^<i>+</i> intestinal stem cells. Notably, the enhanced stem cell activity was observed even in <i>Trpm5</i> knockout mice, suggesting that it is mechanistically independent of TC hyperplasia. Instead, we demonstrated the functional involvement of the gut microbiota, as antibiotic treatment abolished this effect, and fecal material transfer from erythritol-consumed mice replicated the enhancement of stem cell activity in recipient mice. Furthermore, we identified acetate as the metabolite responsible for enhancing stem cell activity. These findings suggest the functional decoupling of TC hyperplasia and the enhancement of stem cell activity, providing a potential therapeutic avenue for gut epithelial diseases.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 3","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}