The FASEB Journal最新文献

{"title":"NOR-1 Overexpression Elevates Myoglobin Expression via PERM1 and Enhances Mitochondrial Function and Endurance in Skeletal Muscles of Aged Mice","authors":"Hector G. Paez,&nbsp;Christopher R. Pitzer,&nbsp;Peter J. Ferrandi,&nbsp;Junaith S. Mohamed,&nbsp;Stephen E. Alway","doi":"10.1096/fj.202500375R","DOIUrl":"https://doi.org/10.1096/fj.202500375R","url":null,"abstract":"<p>Skeletal muscle health and function deteriorate with age, ultimately leading to impaired mobility and disability. Exercise is among the most effective interventions to mitigate muscle dysfunction in aging and reverse deficits. However, low attrition and an impaired capacity to exercise may limit its utility in improving muscle function in aged persons. Therefore, it is crucial to advance our mechanistic understanding of the molecular transducers of exercise to identify new and innovative drug targets to improve muscle health. Transcriptomic profiling of the human response to exercise has revealed that the nuclear receptor NR4A3 (NOR-1) is among the most responsive genes to acute exercise. Previously, we observed that in vitro knockdown of NOR-1 alters metabolic signaling in C2C12 myotubes. Specifically, we found that expression of PERM1, CKMT2, myoglobin, and mTORC1 signaling were perturbed during the knockdown of NOR-1. Herein, we extend these findings and observe that a NOR-1-PERM1-myoglobin axis regulates myoglobin expression in vitro. Furthermore, we found that aging is associated with reduced skeletal muscle NOR-1 expression. Although it is well known that exercise improves aged muscle function, whether overexpression of the exercise-responsive gene NOR-1 can confer benefits and improve muscle function in an aged context has not been evaluated. We found that the overexpression of NOR-1 in aged muscle results in enhanced muscle endurance, mitochondrial respiration, and elevated expression of NOR-1 responsive genes that we previously identified in loss of function studies. However, we also observed that overexpression of NOR-1 did not improve maximal muscle torque production and resulted in a small but significant loss of muscle wet weight that was concomitant with elevated autophagy signaling. Our data suggest that NOR-1 expression may reduce muscle fatigability and that NOR-1 drives myoglobin expression in a PERM1-dependent manner.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500375R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836082","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":"Effect of electroacupuncture at Zusanli reduced Olanzapine-induced lipid disturbances in mice via potential liver-brain interaction","authors":"Jianhua Chen,&nbsp;Peijun Ju,&nbsp;Chao Luo,&nbsp;Sijing Tu,&nbsp;Ying Sun,&nbsp;Si Shi,&nbsp;Genmin Sun,&nbsp;Lixuan Huang,&nbsp;Zhaoqin Wang,&nbsp;Yifeng Xu,&nbsp;Yongyong Shi,&nbsp;Huangan Wu","doi":"10.1096/fj.202402319R","DOIUrl":"https://doi.org/10.1096/fj.202402319R","url":null,"abstract":"<p>Olanzapine-induced weight gain and disruptions in lipid metabolism represent multifactorial processes that compromise treatment adherence in schizophrenia and contribute to substantial clinical challenges. While acupuncture has been reported to promote weight loss, the neural substrates mediating its metabolic effects in olanzapine-induced models remain largely undefined. In this study, we evaluated the efficacy of electroacupuncture (EA) at the Zusanli (ST36) acupoint in ameliorating olanzapine-induced obesity and dyslipidemia, and investigated the underlying liver–brain regulatory mechanisms. We further assessed the effects of EA through Reverse Transcription Polymerase Chain Reaction (RT-PCR), ELISA, and lipidomics analysis. Comprehensive evaluations were conducted using three-dimensional fine behavioral analysis and metabolic cages. Additionally, ultrasound functional imaging (fUS), retrograde tracing with pseudorabies virus 152 (PRV152), and c-Fos mapping techniques were employed to investigate liver-brain interactions. EA at ST36 effectively reduced body weight, reversed Olanzapine-induced adipocyte hypertrophy and hepatocyte damage, and restored disturbances in free fatty acids (FFA) and liver lipid metabolism. These effects also involved the restoration of olanzapine-induced disruptions in respiratory exchange rate (RER) during the dark cycle. We further explored the potential regulatory mechanisms, and we successfully demonstrated that EA stimulation significantly deactivated Agouti-related protein (AGRP)-expressing neurons in the lateral septal nucleus (LS), nucleus accumbens (NAc), and pallidum, suggesting that AGRP+ neurons in these brain regions are involved in the liver-brain interaction during EA treatment. These findings highlight the critical role of metabolism-regulating neurons in the acupuncture-mediated liver-brain axis and provide insights into the mechanisms of information integration from the brain to the liver.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836121","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":"Invertebrate Bile Acid-Sensitive Ion Channels and Their Emergence in Bilateria","authors":"Josep Martí-Solans,&nbsp;Aina Børve,&nbsp;Line Vevle,&nbsp;Andreas Hejnol,&nbsp;Timothy Lynagh","doi":"10.1096/fj.202403216R","DOIUrl":"https://doi.org/10.1096/fj.202403216R","url":null,"abstract":"<div>\u0000 \u0000 <p>The broad Degenerin/epithelial sodium channel (DEG/ENaC) family includes a subfamily of bile acid-sensing ion channels (BASICs). While their biophysical properties are extensively studied in mammals, the presence and function of BASICs in invertebrates remain largely unexplored. Here, we present the first functional evidence of invertebrate BASICs, revealing conserved features and evolutionary adaptations across bilaterian species. Using electrophysiological and pharmacological approaches, we show that invertebrate BASICs exhibit species-specific bile acid sensitivity profiles and differing responses to channel blockers, amiloride, and diminazene, while retaining shared properties like inhibition by calcium ions and selective permeability of sodium ions. For example, the acorn worm <i>Schizocardium californicum</i> BASIC displays broad bile acid sensitivity similar to mammals, while the brachiopod <i>Novocrania anomala</i> BASIC is activated solely by ursodeoxycholic acid (UDCA) in our experiments. Mutagenesis of the conserved D444 residue in the pore-lining region confirms its critical role in gating. Combined functional and phylogenetic analysis suggests BASICs emerged early in bilaterian evolution, evolving from channels that were merely modulated by bile acids, like their acid-sensing ion channel cousins, into channels that are activated by bile acids. Tissue-specific expression patterns imply roles in bile acid-dependent sodium absorption or environmental sensing of bile acid-like compounds. Given the absence of endogenous bile acids in invertebrates, we propose that invertebrate BASICs may detect environmental compounds, contributing to ecological interactions. This study enhances our understanding of the evolutionary, functional, and ecological roles of BASICs, with implications for future research into their native ligands.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836122","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":"Targeting MLL1/WDR5-Mediated Epigenetic Regulation Mitigates Peritoneal Fibrosis by Reducing p16INK4a","authors":"Daisuke Hara,&nbsp;Kensuke Sasaki,&nbsp;Shigehiro Doi,&nbsp;Takeshi Ike,&nbsp;Kazuya Maeda,&nbsp;Maria Yoshida,&nbsp;Akira Takahashi,&nbsp;Yosuke Osaki,&nbsp;Naoki Ishiuchi,&nbsp;Yujiro Maeoka,&nbsp;Toshiki Doi,&nbsp;Takuto Chiba,&nbsp;Ayumu Nakashima,&nbsp;Takao Masaki","doi":"10.1096/fj.202402382R","DOIUrl":"https://doi.org/10.1096/fj.202402382R","url":null,"abstract":"<p>Peritoneal fibrosis poses a significant challenge to the long-term efficacy of peritoneal dialysis (PD), with emerging evidence highlighting the role of cellular senescence in its pathogenesis. p16^INK4a is a cell cycle regulator that has been implicated in cellular senescence. Mixed-lineage leukemia 1 (MLL1) forms a complex with WD-40 repeat protein 5 (WDR5) and exhibits histone H3K4 methyltransferase activity. We have previously shown that inhibition of the MLL1/WDR5 complex reduces p16^INK4a expression and attenuates renal senescence after injury in mice. This study aimed to investigate whether inhibiting MLL1/WDR5 attenuates peritoneal senescence, inflammation, and fibrosis in both human samples and in mice with methylglyoxal (MGO)-induced peritoneal fibrosis (MGO-injected mice), while also exploring the associated underlying mechanisms. MLL1/WDR5, histone 3 lysine 4 trimethylation (H3K4me3), and p16^INK4a expression were elevated in TGF-β1-stimulated human peritoneal mesothelial cells (HPMCs), non-adherent cells obtained from patients undergoing PD, and the submesothelial compact zones of MGO-injected mice. Notably, p16^INK4a expression in these cells was positively correlated with the dialysate/plasma creatinine ratio. Treatment with the MLL1/WDR5 protein–protein interaction inhibitors MM-102 and OICR-9429 reduced H3K4me3 levels and p16^INK4a expression, suppressing fibrosis in HPMCs as well as peritoneal fibrosis and inflammation in MGO-injected mice. These inhibitors also improved peritoneal function in MGO-injected mice. Additionally, we demonstrated that MLL1/WDR5-induced H3K4me3 directly regulates <i>p16</i>^<i>INK4a</i> gene transcription, and that inhibiting MLL1/WDR5 reduces H3K4me3, thereby suppressing <i>p16</i>^<i>INK4a</i> gene transcription. These findings suggest that targeting MLL1/WDR5 activation alleviates peritoneal senescence, inflammation, and fibrosis, highlighting its potential as a promising therapeutic strategy for peritoneal fibrosis.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202402382R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143835919","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":"A Novel Mechanism of the p53 Isoform Δ40p53α in Regulating Collagen III Expression in TGFβ1-Induced LX-2 Human Hepatic Stellate Cells","authors":"Sun-Young Lee,&nbsp;Yunseong Jang,&nbsp;Hye-Yeon Seok,&nbsp;Yong-Hwan Moon","doi":"10.1096/fj.202403146RR","DOIUrl":"https://doi.org/10.1096/fj.202403146RR","url":null,"abstract":"<p>Injured liver cells undergoing chronic wound healing produce excessive amounts of extracellular matrix (ECM) components, such as collagen and fibronectin, leading to fibrosis. This process is largely mediated by transforming growth factor-β (TGFβ) signaling, which intersects with the tumor suppressor p53 pathway. However, the roles of specific p53 isoforms in this interaction remain unclear. In this study, we report the involvement of the Δ40p53α isoform, an N-terminal truncated variant of p53, in regulating ECM gene expression in TGFβ1-activated LX-2 human hepatic stellate cells. RT-PCR analysis of cirrhotic liver tissues revealed clinically relevant increases in Δ40p53 expression. Knockdown of Δ40p53 using antisense oligonucleotides in LX-2 cells attenuated TGFβ1-induced activation and significantly reduced collagen production and deposition, particularly fibrillar collagen III. Conversely, overexpression of Δ40p53α upregulated collagen III expression in concert with full-length p53 (FLp53). Co-immunoprecipitation analysis demonstrated that Δ40p53α forms a complex with FLp53, which associates with phosphorylated Smad3 following TGFβ1 stimulation. These findings suggest that Δ40p53 enhances collagen III expression by interacting with FLp53 and Smads, highlighting its role in profibrogenic ECM expression.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202403146RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143836100","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":"Pathogenesis of Focal Segmental Glomerulosclerosis Caused by a Leu754Val Mutation in ARHGAP32","authors":"Sipei Chen,&nbsp;Li Wang,&nbsp;Yang Zou,&nbsp;Yi Li,&nbsp;Xiang Zhong,&nbsp;Guisen Li","doi":"10.1096/fj.202403242R","DOIUrl":"https://doi.org/10.1096/fj.202403242R","url":null,"abstract":"<div>\u0000 \u0000 <p>Focal segmental glomerulosclerosis (FSGS) shows a poor response to hormones and other treatment schemes and rapidly progresses to end-stage renal disease. Genetic factors are important causes of FSGS. We recently identified a new candidate pathogenic <i>ARHGAP32</i> mutation in a family affected by FSGS and further investigated its functional impact through in vivo and in vitro studies. We established in vitro models of <i>ARHGAP32</i> overexpression in podocytes and COS-7 kidney cells by plasmid transfection. Mice with the point mutation were established using CRISPR/Cas9 technology, followed by the establishment of a kidney injury model by adriamycin administration via the tail vein. The ARHGAP32 protein was found to be expressed in human kidney tissues. Podocytes transfected with mutant <i>ARHGAP32</i> showed a significant decrease in the expression of the podocyte markers nephrin. Similarly, COS-7 cells transfected with mutant <i>ARHGAP32</i> showed decreased expression of the cytoskeletal protein F-actin. The ARHGAP32 mutant protein had 20-fold higher affinity for Cdc42 than the wild-type protein. Adriamycin-induced L405V mutant mice showed slow growth, proteinuria, increased serum creatinine and blood urea nitrogen levels, and pathological kidney damage. RhoA, Rac1, and Cdc42 all showed decreased expression in podocytes overexpressing mutant <i>ARHGAP32</i> and in the kidneys of mutant mice. These findings suggest that the <i>ARHGAP32</i> L754V mutation induces podocyte damage, leading to kidney damage and the potential development of FSGS. This study provides a new basis for elucidating the pathogenesis of FSGS and the exploration of new therapeutic measures.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831004","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":"Amuc_1434 From Akkermansia muciniphila Enhances CD8+ T Cell-Mediated Anti-Tumor Immunity by Suppressing PD-L1 in Colorectal Cancer","authors":"Jiahao Zhu,&nbsp;Shaolei Qin,&nbsp;Ruike Gu,&nbsp;Shengjun Ji,&nbsp;Gang Wu,&nbsp;Ke Gu","doi":"10.1096/fj.202403295RR","DOIUrl":"https://doi.org/10.1096/fj.202403295RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Colorectal cancer (CRC) shows a limited response to programmed death-ligand 1 (PD-L1) immunotherapies. <i>Akkermansia muciniphila</i> (AKK) may enhance tumor immunity. This study examines how its Outer Membrane Vesicles (OMVs) and Amuc_1434 influence PD-L1 expression and CD8+ T cell activity in CRC. OMVs were isolated and their characteristics were examined through transmission electron microscopy and Western blotting. PD-L1 expression was quantified via Western blot, while CD8+ T cell proliferation was measured using flow cytometry. Cytokine production (interferon-gamma (IFN-γ) and interleukin-2 (IL-2)) was evaluated using ELISA. A CRC mouse model was employed to examine its impact on tumor growth and immune cell infiltration. In CRC cells, treatment with AKK-derived OMVs (AKK-OMVs) significantly downregulated PD-L1 expression (<i>p</i> &lt; 0.05) and markedly increased CD8+ T cell proliferation and the levels of IFN-γ and IL-2 (<i>p</i> &lt; 0.01). Amuc_1434 was identified as the key protein mediating these effects. In vivo, AKK-OMVs treatment substantially reduced tumor volume (<i>p</i> &lt; 0.01) and significantly enhanced CD8+ T cell infiltration into the tumor microenvironment (<i>p</i> &lt; 0.01). Additionally, AKK-OMVs-treated mice showed increased expression of immune activation markers within the tumor tissue, further indicating enhanced antitumor immunity. This study reveals that AKK-OMVs, particularly those containing Amuc_1434, can modulate PD-L1 expression and potentiate CD8+ T cell-mediated antitumor immunity in CRC. These findings suggest a novel approach to overcoming resistance to immune checkpoint inhibitors in CRC.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 8","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831007","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":"Identification of CDKN1A as a potential key risk factor in MASLD progression","authors":"Lijuan Deng,&nbsp;Jianxin Deng,&nbsp;Liping Luo,&nbsp;Hongjia Yang,&nbsp;Mengxue Sun,&nbsp;Yucheng Gao,&nbsp;Qing Liu,&nbsp;Ebenezeri Erasto Ngowi,&nbsp;Yinghua Zhou,&nbsp;Rongrong Zhang,&nbsp;Xiaojun Liu,&nbsp;Aijun Qiao","doi":"10.1096/fj.202402942R","DOIUrl":"https://doi.org/10.1096/fj.202402942R","url":null,"abstract":"<p>Metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is recognized as a highly heterogeneous condition. The elusive mechanisms driving its progression contribute to the lack of reliable diagnostic markers and effective treatments. In this study, we first identified 52 differentially expressed genes (DEGs) in MASLD stage by analyzing two public datasets, GSE126848 and GSE135251, using the DESeq2 and edgeR packages. Subsequently, these DEGs were subjected to protein–protein interaction (PPI) network analysis, revealing the top 10 hub genes. By intersecting the top 10 hub genes with another public dataset GSE260222, we observed that CDKN1A was the sole gene consistently upregulated in the livers of MASLD patients across all analyses. The elevated protein expression of CDKN1A was further validated in the livers of MASLD patients compared to control subjects. Consistently, compared to their respective control groups, both CDKN1A mRNA and protein levels were dramatically increased in the livers of MASLD animal models, including high-fat diet (HFD) induced obese mice, leptin-deficient obese (<i>ob/ob</i>) mice and leptin receptor-deficient (<i>db/db</i>) mice, and in mouse primary hepatocytes treated with free fatty acids (FFA), respectively. Interestingly, we found that CDKN1A transcript levels were progressively and significantly increased with the severity of MASLD in four out of five datasets and positively correlated with both the NAFLD activity score (NAS) and fibrosis stage, two important clinicopathological features of MASLD. Collectively, our results illustrated that CDKN1A may serve as a promising biomarker and therapeutic target for MASLD; however, its role in the disease's pathology warrants further investigation.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818678","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":"Luteolin Modulate Endoplasmic Reticulum Stress by Targeting SIRT1 to Ameliorate DSS-Induced Ulcerative Colitis in Mice","authors":"Hai-Xiang Guo,&nbsp;Zhong-Hao Ji,&nbsp;Bing-Bing Wang,&nbsp;Yu Xiao,&nbsp;Jin-Ping Hu,&nbsp;Yi Zheng,&nbsp;Wei Gao,&nbsp;Bao Yuan","doi":"10.1096/fj.202403418R","DOIUrl":"https://doi.org/10.1096/fj.202403418R","url":null,"abstract":"<div>\u0000 \u0000 <p>Ulcerative colitis (UC) is a recurrent, chronic disease whose main symptoms include weight loss, diarrhea, and blood in the stool. In recent years, the incidence of UC has been increasing year by year, which seriously affects the daily life of patients. Luteolin (Lut), as a flavonoid, is widely found in a variety of vegetables and fruits and has been shown to have a variety of pharmacological activities. This work investigated the effects of Lut on dextrose sodium sulfate (DSS)-induced ulcerative colitis (UC) in mice, with a special focus on the role of endoplasmic reticulum (ER) stress in this. The outcomes demonstrated that colitis symptoms, including disease phenotype, elevated inflammatory factor levels, intestinal barrier damage, and gut microbiota disruption, were considerably alleviated in UC model mice treated with luteolin. Also, Lut alleviated ER stress and apoptosis in UC mice. We then explored the effects of Lut on ER stress and apoptosis induced by thapsigargin (TG) and tunicamycin (TM) in HT29 cells in vitro. It was found that Lut treatment inhibited TM/TG-induced ER stress and apoptosis. However, these inhibitory effects of Lut were attenuated by SIRT1 silencing in TM-treated HT29 cells. In conclusion, our results suggest that Lut supplementation in a mouse model of colitis improves the symptoms of colitis in mice, which provides a theoretical basis for further application of Lut in the prevention of inflammation-related diseases in humans.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809685","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":"Muscle-Derived miR-200a-3p Through Light-Intensity Exercise May Contribute to Improve Memory Dysfunction in Type 2 Diabetic Mice","authors":"Takeru Shima,&nbsp;Hayate Onishi,&nbsp;Chiho Terashima","doi":"10.1096/fj.202500336R","DOIUrl":"https://doi.org/10.1096/fj.202500336R","url":null,"abstract":"<p>Memory dysfunction associated with type 2 diabetes mellitus (T2DM) poses a threat to well-being. Engaging in light-intensity exercise has favorable effects on hippocampal function and molecular profiles, including <i>Mct2</i> mRNA and miR-200a-3p. Here, we investigated the involvement of exosomal miR-200a-3p secretion from gastrocnemius muscles in T2DM mice undergoing light-intensity exercise intervention, focusing on its potential to ameliorate memory dysfunction. We initially assessed the effects of light-intensity exercise over a 4-week period on memory function, the secretion of gastrocnemius muscle-derived exosomal miR-200a-3p, and hippocampal mRNA. Subsequently, the impact of a daily intraperitoneal injection of the mmu-miR-200a-3p mimic over a 4-week duration on hippocampal dysregulation in ob/ob mice was investigated. The light-intensity exercise intervention improved gastrocnemius muscle-derived and plasma exosomal miR-200a-3p levels in ob/ob mice, concomitant with improved memory dysfunction. Intriguingly, the daily intraperitoneal injection of the mmu-miR-200a-3p mimic also improved memory function in ob/ob mice. Notably, both the exercise intervention and miR-200a-3p mimic treatment induced downregulation in hippocampal <i>Keap1</i> and upregulation in <i>Hsp90aa1</i> and <i>Mct2</i> mRNA in ob/ob mice. These results imply that the augmentation of peripherally derived miR-200a-3p contributes to ameliorating memory dysfunction in T2DM mice undergoing light-intensity exercise, with a possible contribution from gastrocnemius muscle-derived exosomal miR-200a-3p to these exercise effects.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 7","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500336R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809686","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}