The FASEB Journal最新文献_第10页

Imperatorin Mitigates Rosacea-Like Inflammation by Modulating the Crosstalk Between JNK1 and STAT1 欧前胡素通过调节JNK1和STAT1之间的串扰减轻酒糟样炎症。

IF 4.2 2区生物学

The FASEB Journal Pub Date : 2026-03-03 DOI: 10.1096/fj.202503868RR

Xiaoxue Wang, Zexin Zhu

{"title":"Imperatorin Mitigates Rosacea-Like Inflammation by Modulating the Crosstalk Between JNK1 and STAT1","authors":"Xiaoxue Wang, Zexin Zhu","doi":"10.1096/fj.202503868RR","DOIUrl":"10.1096/fj.202503868RR","url":null,"abstract":"<p>Rosacea is a chronic inflammatory dermatological disorder involving the activation of various signaling pathways. Imperatorin (IMP), a coumarin compound, has been documented to exhibit anti-inflammatory properties. Nevertheless, its therapeutic efficacy in managing rosacea remains unexplored. Bioinformatics and network pharmacology approaches were utilized to elucidate potential signaling pathways and molecular targets of IMP in the context of rosacea. Subsequently, to assess the in vivo therapeutic efficacy of IMP, murine models exhibiting rosacea-like inflammatory responses were developed. Additionally, in vitro experiments were conducted to elucidate the molecular mechanisms underlying the anti-rosacea effects of IMP. Our findings demonstrated that both intraperitoneal and topical administration of IMP significantly attenuated skin inflammation in mice with LL37-induced rosacea models. Mechanistic investigations, guided by bioinformatics and network pharmacology analyses, revealed an interaction between JNK1 and STAT1. IMP was found to directly bind to JNK1 and STAT1, disrupting their interaction, thereby inhibiting STAT1 phosphorylation and nuclear translocation. This inhibition resulted in decreased production of STAT1-mediated inflammatory mediators in keratinocytes. These results suggest that IMP may serve as a promising therapeutic agent for inflammatory skin diseases by targeting the crosstalk between JNK1 and STAT1.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12955509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147345655","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}

引用次数: 0

Integrated Proteomics and Metabolomics Analysis in Hippocampus of Rats With T2DM-Associated Cognitive Decline t2dm相关认知衰退大鼠海马综合蛋白质组学和代谢组学分析

IF 4.2 2区生物学

The FASEB Journal Pub Date : 2026-03-02 DOI: 10.1096/fj.202503916R

Ying Zhang, Jiale Yu, Dongmei Su, Li Hou, Bin He, Huiping Wang, Cuige Shi

{"title":"Integrated Proteomics and Metabolomics Analysis in Hippocampus of Rats With T2DM-Associated Cognitive Decline","authors":"Ying Zhang, Jiale Yu, Dongmei Su, Li Hou, Bin He, Huiping Wang, Cuige Shi","doi":"10.1096/fj.202503916R","DOIUrl":"10.1096/fj.202503916R","url":null,"abstract":"<div>\u0000 \u0000 <p>Type 2 diabetes mellitus (T2DM) is currently one of the most prominent and global chronic conditions. Cognitive decline is one of the major complications of T2DM, but its precise molecular mechanism remains unclear. Metabolomics and proteomics were combined in this study to investigate alterations in metabolites and proteins in the hippocampus of T2DM rats. KEGG Markup Language (KGML) network analysis was conducted to integrate underlying relationships among differentially expressed metabolites and proteins. 58 significantly differentially expressed metabolites and 61 differentially expressed proteins were identified between T2DM and CON rats. In proteomic analysis, GO analysis showed that DEPs involved in biological process were mainly related to neurofilament cytoskeleton organization, postsynaptic actin cytoskeleton organization and actin filament severing. KEGG pathway analysis showed the major enriched pathways were thiamine metabolism, cholesterol metabolism, pentose phosphate pathway (PPP), ABC transporters and regulation of actin cytoskeleton. In metabolomics analysis, KEGG pathway analysis showed the major enriched pathways were autophagy, lysosome, glycolysis/gluconeogenesis, PPP and ABC transporters. KGML network analysis revealed that PPP and ABC transporters were activated in the hippocampus of T2DM rats, accompanied by the up-regulation of metabolites in two pathways. Rpia was up-regulated, which is the indicator of increased PPP flux. Tap1, the unique immune-function ABC transporter, was up-regulated. Excessive PPP activation disrupts cognition-related synaptic transmission, while up-regulated immune-function ABC transporters drive aberrant synaptic remodeling and chronic neuroinflammation. These results provide a better understanding of biological mechanisms underlying T2DM-related cognitive dysfunction and may help identify potential targets for neuroprotective drugs against cognitive dysfunction in T2DM.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147345636","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}

引用次数: 0

Frequent Loss of CACNA1C Is Associated With Poor Prognosis in Non-Small Cell Lung Cancer. 非小细胞肺癌中频繁的CACNA1C缺失与不良预后相关

IF 4.2 2区生物学

The FASEB Journal Pub Date : 2026-02-28 DOI: 10.1096/fj.202504868R

Saanvi Dasgupta, Sapthala L Galappaththi, Rajarshi Banerjee, Enas S Alsatari, Paramahansa Pramanik, Stephen M Marbut, Furhan Yunus, Jose N Galeas, Santanu Dasgupta

{"title":"Frequent Loss of CACNA1C Is Associated With Poor Prognosis in Non-Small Cell Lung Cancer.","authors":"Saanvi Dasgupta, Sapthala L Galappaththi, Rajarshi Banerjee, Enas S Alsatari, Paramahansa Pramanik, Stephen M Marbut, Furhan Yunus, Jose N Galeas, Santanu Dasgupta","doi":"10.1096/fj.202504868R","DOIUrl":"10.1096/fj.202504868R","url":null,"abstract":"<p><p>Lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) are common histologic subtypes of non-small cell lung cancer (NSCLC), usually diagnosed at advanced stages with a dismal survival rate. A high-resolution SNP array (Affymetrix 250 NspI) analysis of five primary NSCLC tumors and their follow-up mucosal biopsies (n = 25) identified frequent copy neutral loss of heterozygosity (LOH, loss of 59 SNPs) of CACNA1C, a calcium voltage-gated channel subunit. Transcriptomic profiling utilizing The Cancer Genome Atlas (TCGA) revealed frequent loss of mRNA expression of CACNA1C in LUAD and LUSC tumors compared to the normal counterparts. Loss of CACNA1C mRNA expression was significantly associated with stage, grade, lymph node metastasis, P53 gene mutation, and the worst survival of these patients. We also recorded significantly higher promoter methylation of CACNA1C in the tumors compared to the normal counterparts. Increased level of promoter hypermethylation of CACNA1C was significantly associated with stage, grade, lymph node metastasis, P53 gene mutation, and poor survival of the patients. We also identified frequent mutations in CACNA1C among the NSCLC patients, which were associated with immune function modulation. Analysis of an independent cohort of NSCLC subjects revealed significant loss of CACNA1C protein expression in primary tumors (n = 31) and lymph node metastases (n = 10) compared to normal tissues. Loss of CACNA1C protein expression appeared to be an early event in LUAD patients. Further validation of CACNA1C expression in larger cohorts and functional characterization would be beneficial for potential biomarkers and therapeutic development.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 4","pages":"e71614"},"PeriodicalIF":4.2,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147272700","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}

引用次数: 0

LncRNA IGF2AS Regulates Bovine Adipocyte Differentiation by Stabilizing the ILF3/FTO Complex and Activating PI3K/AKT Signaling LncRNA IGF2AS通过稳定ILF3/FTO复合物和激活PI3K/AKT信号通路调控牛脂肪细胞分化。

IF 4.2 2区生物学

The FASEB Journal Pub Date : 2026-02-28 DOI: 10.1096/fj.202505066R

Chengchuang Song, Junhao Chen, Xingyue Jiang, Binglan Chen, Yi Pan, Chenyang Su, Jing Ren, Xiaoyan Li, Xi Chen, Yanhong Wang, Xingtang Fang, Chunlei Zhang

{"title":"LncRNA IGF2AS Regulates Bovine Adipocyte Differentiation by Stabilizing the ILF3/FTO Complex and Activating PI3K/AKT Signaling","authors":"Chengchuang Song, Junhao Chen, Xingyue Jiang, Binglan Chen, Yi Pan, Chenyang Su, Jing Ren, Xiaoyan Li, Xi Chen, Yanhong Wang, Xingtang Fang, Chunlei Zhang","doi":"10.1096/fj.202505066R","DOIUrl":"10.1096/fj.202505066R","url":null,"abstract":"<div>\u0000 \u0000 <p>In our previous study, we identified IGF2AS, an antisense long noncoding RNA transcript of insulin-like growth factor 2, as a critical regulator of bovine skeletal muscle development. Subsequent investigation revealed its differential expression pattern during bovine preadipocyte differentiation, though its functional significance remained unclear. Through gain- and loss-of-function experiments, we demonstrated that IGF2AS overexpression enhances adipogenic gene expression and promotes fat deposition, while its knockdown produces opposing effects. Mechanistically, RNA-seq analysis following IGF2AS silencing revealed significant downregulation of PI3K/AKT signaling pathway components. Furthermore, RNA immunoprecipitation (RIP) and co-immunoprecipitation (Co-IP) assays identified physical interactions between IGF2AS and the ILF3/FTO protein complex, suggesting a novel regulatory axis through which IGF2AS modulates PI3K/AKT-mediated adipogenesis in bovine adipocytes. These findings not only elucidate a previously unrecognized mechanism of lncRNA-mediated fat deposition regulation but also position IGF2AS as a potential molecular target for precision breeding strategies aimed at improving beef quality.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147318887","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}

引用次数: 0

Gut Microbial Secondary Metabolites of Bile Acids and Amino Acids Regulate Th1/Th2 Immune Modulation in Unexplained Infertility: A Multiomics and Cohort Analysis Approach. 肠道微生物胆汁酸和氨基酸次级代谢物调节不明原因不孕症的Th1/Th2免疫调节：多组学和队列分析方法

IF 4.2 2区生物学

The FASEB Journal Pub Date : 2026-02-28 DOI: 10.1096/fj.202504204R

Chong Ma, Xiaofeng Ye, Wenqi Guo, Ruirui Zhao, Sihang Zhou, Hao Li, Yanjun Hong, Liping Wang, Zhiyong Xie

{"title":"Gut Microbial Secondary Metabolites of Bile Acids and Amino Acids Regulate Th1/Th2 Immune Modulation in Unexplained Infertility: A Multiomics and Cohort Analysis Approach.","authors":"Chong Ma, Xiaofeng Ye, Wenqi Guo, Ruirui Zhao, Sihang Zhou, Hao Li, Yanjun Hong, Liping Wang, Zhiyong Xie","doi":"10.1096/fj.202504204R","DOIUrl":"10.1096/fj.202504204R","url":null,"abstract":"<p><p>Unexplained Infertility (UI) is a complex condition of elusive etiology, where the interplay between immune dysregulation and metabolic disturbances remains poorly understood. We hypothesized that gut microbiota-derived metabolites act as central modulators of the systemic immune and metabolic balance in UI patients. We employed an integrated multiomics approach, combining metabolomics, gut microbiome analysis, and immune profiling, in a cross sectional discovery cohort (47 UI patients and 53 healthy controls), and validated key findings in an independent cohort (37 UI patients and 39 healthy controls). Our findings demonstrated that UI patients exhibited a proinflammatory Th1-dominant immune profile, marked by elevated proinflammatory cytokines and reduced anti-inflammatory IL-10. This immune imbalance was accompanied by a deficiency in protective gut-derived secondary metabolites, notably secondary bile acids and phenylpropanoic acid. Furthermore, gut microbiota analysis revealed significant dysbiosis (increased pathogenic taxa and decreased beneficial microbes) and a functional deficiency in the aromatic amino acid metabolism gene cluster, explaining the observed metabolite scarcity. Mechanistically, in vitro assays and network pharmacology indicated that these metabolites directly modulate the Th1/Th2 immune balance by regulating a core host network centered on TNF, PPARG, and PTGS2. In summary, our data reveal the role of a novel gut microbiota-metabolite-immune axis in UI pathophysiology, where a deficiency in protective gut-derived secondary metabolites contributes directly to systemic immune dysregulation and a proinflammatory state. These metabolites serve as potential candidates for future evaluation and represent promising therapeutic targets for interventions to restore immune homeostasis in UI patients.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 4","pages":"e71573"},"PeriodicalIF":4.2,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147286190","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}

引用次数: 0

High Dietary Carbonyl Iron Reshapes the Gut Microbiome and Impairs Hepatic Insulin Sensitivity in a Time-Dependent Manner. 高羰基铁饮食重塑肠道微生物群和损害肝脏胰岛素敏感性在一个时间依赖的方式。

IF 4.2 2区生物学

The FASEB Journal Pub Date : 2026-02-28 DOI: 10.1096/fj.202504722R

Yupeng Li, Carine Fillebeen, Sinan Li, Jiarui Chen, Gary Sweeney, Kostas Pantopoulos

{"title":"High Dietary Carbonyl Iron Reshapes the Gut Microbiome and Impairs Hepatic Insulin Sensitivity in a Time-Dependent Manner.","authors":"Yupeng Li, Carine Fillebeen, Sinan Li, Jiarui Chen, Gary Sweeney, Kostas Pantopoulos","doi":"10.1096/fj.202504722R","DOIUrl":"10.1096/fj.202504722R","url":null,"abstract":"<p><p>The gut microbiome is widely viewed as an important regulator of host metabolism and immunity. Loss of microbial diversity can lead to gut dysbiosis, which has been linked to cardiometabolic and inflammatory disorders. Iron is an important micronutrient for both host and microbes, but its excess is toxic. To investigate the impact of dietary iron on the intestinal microbiome and host metabolism, wild type mice on standard chow were switched at baseline to a high-iron diet, containing 2% carbonyl iron for 3 weeks. Other groups of mice were switched to the high-iron diet only during the final 3 or 7 days of the 3-week period; control animals remained on standard chow. Fecal samples were collected at baseline (t = 0) and at the endpoint (t = 1) for microbiome analysis, while liver and skeletal muscle samples were analyzed for Akt phosphorylation as a marker of insulin sensitivity. Feeding with high carbonyl iron significantly altered the intestinal microbiome and increased overall alpha and beta diversity in a time-dependent manner. Differential abundance and network analyses revealed extensive taxonomic and structural reorganization, with notable increases in Akkermansiaceae, Rikenellaceae, Bilophila, Ruminiclostridium, and Lactobacillus, and decreases in Bifidobacteriaceae and Clostridiaceae_1. Iron overload was accompanied by reduced Akt phosphorylation, evident in the liver but not skeletal muscles at the 3-week endpoint. Together, these results demonstrate that feeding of mice with a high carbonyl iron diet reshapes gut microbial composition, increases diversity, and reorganizes microbial community networks. However, iron overload mitigates insulin responsiveness in the liver.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 4","pages":"e71626"},"PeriodicalIF":4.2,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12930339/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147277581","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}

引用次数: 0

Inhibition of DNA Methyltransferase 1 Ameliorates Renal Injuries in Diabetic Nephropathy by Targeting NF2 抑制DNA甲基转移酶1通过靶向NF2改善糖尿病肾病的肾损伤

IF 4.2 2区生物学

The FASEB Journal Pub Date : 2026-02-28 DOI: 10.1096/fj.202504594R

Xiaoqian Zhang, Yanling Song, Xiaofei Huang, Xuan Wang, Weijie Yuan, Nan Zhu

{"title":"Inhibition of DNA Methyltransferase 1 Ameliorates Renal Injuries in Diabetic Nephropathy by Targeting NF2","authors":"Xiaoqian Zhang, Yanling Song, Xiaofei Huang, Xuan Wang, Weijie Yuan, Nan Zhu","doi":"10.1096/fj.202504594R","DOIUrl":"10.1096/fj.202504594R","url":null,"abstract":"<div>\u0000 \u0000 <p>Aberrant DNA methylation patterns have been linked to diverse pathological conditions, including chronic kidney diseases. However, it remains unclear whether DNA methyltransferase 1 (DNMT1) affects renal tubular function in diabetic nephropathy (DN) DNMT1 and neurofibromatosis type 2 (NF2) expression levels were assessed using quantitative real-time PCR, Western blotting, immunohistochemical, and immunofluorescence analyses. The methylation status of the NF2 promoter was assessed through methylation-specific PCR and bisulfite genomic sequencing PCR. Cell viability was evaluated using the MTT assay, and cell apoptosis was quantified through flow cytometry analysis. Additionally, inflammatory responses were evaluated by quantifying IL-1β and IL-6 concentrations with enzyme-linked immunosorbent assays. DNMT1 expression was markedly elevated in the renal samples of DN patients and db/db mice. The DNA methylation inhibitor 5-aza-2′-deoxycytidine alleviated kidney tubular injury in db/db mice, and it also reduced inflammatory responses and cell apoptosis in HK-2 cells exposed to high glucose (HG). Hypermethylation of the NF2 promoter was observed in HK-2 cells exposed to HG. Furthermore, DNMT1 knockdown was found to protect against cell apoptosis and inflammatory injury by modulating NF2 expression. These results demonstrated that DNMT1 can inhibit renal tubular cell apoptosis and inflammation in DN by regulating NF2 expression, which may have therapeutic applications in the development and treatment of DN.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147318912","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}

引用次数: 0

Senescent-Like Myofibers Contribute to Anti-Regenerative Cytokine Signaling in Duchenne Muscular Dystrophy. 衰老样肌纤维参与杜氏肌营养不良的抗再生细胞因子信号传导。

IF 4.2 2区生物学

The FASEB Journal Pub Date : 2026-02-28 DOI: 10.1096/fj.202500098R

Masanari Ikeda, Yukie Tanaka, Hidetoshi Sugihara, Takashi Matsuwaki, Keitaro Yamanouchi

{"title":"Senescent-Like Myofibers Contribute to Anti-Regenerative Cytokine Signaling in Duchenne Muscular Dystrophy.","authors":"Masanari Ikeda, Yukie Tanaka, Hidetoshi Sugihara, Takashi Matsuwaki, Keitaro Yamanouchi","doi":"10.1096/fj.202500098R","DOIUrl":"10.1096/fj.202500098R","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a genetic muscular disease characterized by progressive muscle degeneration. p16 is expressed in skeletal muscles and induces cellular senescence in a rat model of DMD, whereas its ablation enhances muscle regeneration. However, the mechanism underlying this phenomenon remains unclear. This study aimed to elucidate the mechanism for p16-induced DMD exacerbation. RNA-seq analysis revealed p16-dependent upregulation of cytokine gene expression in DMD rat skeletal muscles, which also altered the systemic blood cytokine profile. Furthermore, the effect of an altered humoral environment on muscle regeneration was assessed using the transplanted extensor digitorum longus muscle. Regeneration of grafted muscles from wild-type rats was suppressed in DMD rats but was significantly improved by p16 ablation. Notably, p16 was expressed in the myofibers of DMD rats, and enzymatically isolated myofibers from DMD rats also showed p16-dependent cytokine expression. Thus, cytokines secreted by senescent-like myofibers mediate the anti-regenerative niche in DMD rats, uncovering a novel mechanism for disease progression and potential therapeutic targets.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 4","pages":"e71567"},"PeriodicalIF":4.2,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12926723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147272750","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}

引用次数: 0

Disruption of Hepatic Insulin Signaling Causes Phospholipid Dysregulation in Mice. 肝胰岛素信号的破坏导致小鼠磷脂失调。

IF 4.2 2区生物学

The FASEB Journal Pub Date : 2026-02-28 DOI: 10.1096/fj.202504306R

Quan Pan, Meixia Pan, Weiqi Ai, Wanbao Yang, Wen Jiang, Xianlin Han, Shaodong Guo

{"title":"Disruption of Hepatic Insulin Signaling Causes Phospholipid Dysregulation in Mice.","authors":"Quan Pan, Meixia Pan, Weiqi Ai, Wanbao Yang, Wen Jiang, Xianlin Han, Shaodong Guo","doi":"10.1096/fj.202504306R","DOIUrl":"10.1096/fj.202504306R","url":null,"abstract":"<p><p>Phospholipids are important components of the bilayer of biological membranes. Alterations of phospholipids are associated with metabolic disorders, including insulin resistance. However, how impaired insulin signaling impacts phospholipids has not been well established. Disruption of hepatic insulin signaling is achieved by insulin receptor substrate 1 (IRS1) and IRS2 double deletion (DKO) in the liver. Further deletion of TGF-β1 or Foxo1 in the liver of DKO mice was used to examine the role of TGF-β1 or Foxo1 in contributing to the alterations of phospholipid metabolism in DKO mice. Disruption of hepatic insulin signaling led to the dysregulation of phospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), sphingomyelin (SM), cardiolipin (CL), and lysophospholipids in the liver. Mechanistically, disruption of hepatic insulin signaling dysregulated the expression of genes related to phospholipid metabolism. Interestingly, further deletion of Tgfb1 in the liver of DKO mice (TKObeta1) attenuated the alterations of phospholipids and rescued the abnormal expression of genes related to phospholipid metabolism. Moreover, deletion of transcription factor Foxo1, a key mediator of insulin signaling, achieved similar beneficial effects as Tgfb1 deletion in DKO mice. Our study suggests that insulin signaling plays a crucial role in maintaining phospholipids balance in the liver via TGF-β1 or Foxo1. Targeting TGF-β1 or Foxo1 could be promising strategies to combat phospholipids alterations and related metabolic dysfunctions.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 4","pages":"e71613"},"PeriodicalIF":4.2,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12931579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147286178","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}

引用次数: 0

Maternal O-GlcNAc Transferase Is Required for the Asymmetry of Epigenetic Modifications in Mouse Zygotes. 母体O-GlcNAc转移酶是小鼠受精卵表观遗传修饰不对称的必要条件。

IF 4.2 2区生物学

The FASEB Journal Pub Date : 2026-02-28 DOI: 10.1096/fj.202503577RR

Haoxue Wang, Dan Liu, Shinnosuke Honda, Shuntaro Ikeda

{"title":"Maternal O-GlcNAc Transferase Is Required for the Asymmetry of Epigenetic Modifications in Mouse Zygotes.","authors":"Haoxue Wang, Dan Liu, Shinnosuke Honda, Shuntaro Ikeda","doi":"10.1096/fj.202503577RR","DOIUrl":"10.1096/fj.202503577RR","url":null,"abstract":"<p><p>After fertilization in mammals, there is an epigenetic asymmetry reflected by differences in DNA demethylation and histone modifications between female and male pronuclei (FPN and MPN, respectively). Based on its expression level and amount, we investigated the role of maternal O-GlcNAc transferase (OGT), a key enzyme mediating O-GlcNAcylation, in regulating this asymmetry. By using a specific small-molecule inhibitor and small interfering RNA (siRNA)-mediated knockdown of OGT during oocyte maturation in mice, we evaluated the downstream effects on epigenetic modifications and early developmental capability. OGT inhibition significantly reduced fertilization rates and led to developmental arrest at the zygote or 2-cell stage, whereas the siRNA-mediated decrease of Ogt mRNA had less or no significant effect on preimplantation development. Immunostaining analyses revealed that OGT inhibition reduced 5-hydroxymethylcytosine levels in MPN, attributed to a reduction in Tet methylcytosine dioxygenase 3. In contrast, FPN showed delayed epigenetic changes, with the loss of 5-methylcytosine protection mediated by H3K9me2. Moreover, OGT inhibition increased histone methylation levels in MPN and disrupted epigenetic and size asymmetry between FPN and MPN. These alterations suggest that maternal OGT regulates multiple layers of epigenetic reprogramming in early zygotes. Taken together, these findings suggest that maternal OGT is essential for maintaining epigenetic asymmetry between parental pronuclei, primarily by modulating DNA demethylation and histone methylation in MPN.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 4","pages":"e71592"},"PeriodicalIF":4.2,"publicationDate":"2026-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12927537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147272685","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}

引用次数: 0