Journal of Advanced Research最新文献

{"title":"Insulin-like growth factor binding protein 7 identified in aged dental pulp by single-cell RNA sequencing","authors":"Zhongchun Tong ,&nbsp;Jie Wu ,&nbsp;Qimei Gong ,&nbsp;Yifang Yuan ,&nbsp;Shengchao Wang ,&nbsp;Wenkai Jiang","doi":"10.1016/j.jare.2024.12.018","DOIUrl":"10.1016/j.jare.2024.12.018","url":null,"abstract":"<div><h3>Introduction</h3><div>Aging influences the regenerative and reparative functions of dental pulp, and an in-depth and complete understanding of aged dental pulp is highly important.</div></div><div><h3>Objective</h3><div>This study aimed to explore the heterogeneity of young and aged dental pulp tissue via single-cell RNA sequencing (scRNA-seq), search novel markers of aged dental pulp, and further explore their mechanism.</div></div><div><h3>Methods</h3><div>ScRNA-seq was employed to analyze the heterogeneity of young and aged dental pulp tissue, and immunohistochemical staining was used to detect new marker Insulin-like Growth Factor Binding Protein 7 (IGFBP7) in aged dental pulp. Differentially expressed genes (DEGs) between young and aged dental pulp tissue related with senescence-associated secretory phenotype (SASP) were validated in aging model of H₂O₂-induced dental pulp fibroblast (DPF). The effect of IGFBP7 on cellular senescence were validated by SA-β-Gal, γ-H2AX, and F-actin cytoskeletal staining. RNA-seq was used to analyze the mechanism of IGFBP7 alleviating senescence of H₂O₂-induced DPFs.</div></div><div><h3>Results</h3><div>A total of 32,012 cells were sequenced from 8 dental pulp samples and categorized into 8 main clusters, including fibroblasts (FB), endothelial cells, monocytes, T cells, B cells, mesenchymal stem cells, Schwann cells, and nonmyelinating ScCs. The ratio of fibroblasts was the highest, and FB1 was the largest subcluster of fibroblasts in the young group. In aged dental pulp, the ratio of fibroblasts was relatively low, and fibroblasts had more cellular communication with other cell types in fibroblast growth factor (FGF) and insulin-like growth factor (IGF) signal pathways. IGFBP7 was significantly upregulated in the aged group. Recombinant IGFBP7 reduced the senescence of H₂O₂-induced DPFs.</div></div><div><h3>Conclusions</h3><div>These findings offer insights into the mechanisms of dental pulp aging and enhance our understanding of dental pulp at the single-cell level. Further comprehensive studies are required to clarify the exact mechanisms through which IGFBP7 influences dental pulp aging.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 371-385"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin proteasome system in cardiac fibrosis","authors":"Linqi Zeng ,&nbsp;Xiaokai Zhang ,&nbsp;Zihang Huang ,&nbsp;Shuai Song ,&nbsp;Mohan Li ,&nbsp;Tongyao Wang ,&nbsp;Aijun Sun ,&nbsp;Junbo Ge","doi":"10.1016/j.jare.2024.12.006","DOIUrl":"10.1016/j.jare.2024.12.006","url":null,"abstract":"<div><h3>Background</h3><div>Cardiac fibrosis, including reactive fibrosis and replacement fibrosis, is a common pathological process in most cardiovascular diseases. The ubiquitin proteasome system (UPS) plays an important role in the development of fibrosis by mediating the degradation and synthesis of proteins involved in transforming growth factor-β (TGF-β)-dependent and TGF-β-independent fibrous pathways.</div></div><div><h3>Aim of review</h3><div>This review aims to provide an overview of ubiquitinated and deubiquitinated molecules that participating in cardiac fibrosis, with the ultimate purpose to identify promising targets for therapeutic strategies.</div></div><div><h3>Key scientific concepts of review</h3><div>The UPS primarily impacts cardiac fibrosis through modulation of the TGF-β signaling pathway targeting key molecules involved, including the TGF-β receptors, Smad2/3/4 complexes, and inhibitory Smad7, thereby influencing fibrotic processes. In addition to its effect on TGF-β signaling, UPS also regulates pro-fibrotic pathways independent of TGF-β, including p53, AKT1-p38, and JNK1/2. Understanding these pathways is critical due to their involvement in diverse fibrotic mechanisms. The interplay between ubiquitination and deubiquitination of crucial pathways and molecules is pivotal in cardiac fibrosis and represents a promising area for identifying novel therapeutic targets. Different types of cardiac fibrosis involve distinct fibrotic pathways, leading to differential effects of ubiquitin ligases (E3 ligases) and deubiquitinating enzymes (DUBs) across various cardiac fibrotic diseases. Insights into UPS-mediated regulation of cardiac fibrosis provide potential anti-fibrotic therapeutic strategies, emphasizing the importance of targeting UPS components specific to the heart for effective therapy against cardiac fibrosis.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 501-510"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking biological insights from differentially expressed genes: Concepts, methods, and future perspectives","authors":"Huachun Yin ,&nbsp;Hongrui Duo ,&nbsp;Song Li ,&nbsp;Dan Qin ,&nbsp;Lingling Xie ,&nbsp;Yingxue Xiao ,&nbsp;Jing Sun ,&nbsp;Jingxin Tao ,&nbsp;Xiaoxi Zhang ,&nbsp;Yinghong Li ,&nbsp;Yue Zou ,&nbsp;Qingxia Yang ,&nbsp;Xian Yang ,&nbsp;Youjin Hao ,&nbsp;Bo Li","doi":"10.1016/j.jare.2024.12.004","DOIUrl":"10.1016/j.jare.2024.12.004","url":null,"abstract":"<div><h3>Background</h3><div>Identifying differentially expressed genes (DEGs) is a core task of transcriptome analysis, as DEGs can reveal the molecular mechanisms underlying biological processes. However, interpreting the biological significance of large DEG lists is challenging. Currently, gene ontology, pathway enrichment and protein–protein interaction analysis are common strategies employed by biologists. Additionally, emerging analytical strategies/approaches (such as network module analysis, knowledge graph, drug repurposing, cell marker discovery, trajectory analysis, and cell communication analysis) have been proposed. Despite these advances, comprehensive guidelines for systematically and thoroughly mining the biological information within DEGs remain lacking.</div></div><div><h3>Aim of review</h3><div>This review aims to provide an overview of essential concepts and methodologies for the biological interpretation of DEGs, enhancing the contextual understanding. It also addresses the current limitations and future perspectives of these approaches, highlighting their broad applications in deciphering the molecular mechanism of complex diseases and phenotypes. To assist users in extracting insights from extensive datasets, especially various DEG lists, we developed DEGMiner (<span><span>https://www.ciblab.net/DEGMiner/</span><svg><path></path></svg></span>), which integrates over 300 easily accessible databases and tools.</div></div><div><h3>Key scientific concepts of review</h3><div>This review offers strong support and guidance for exploring DEGs, and also will accelerate the discovery of hidden biological insights within genomes.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 135-157"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exercise-driven cellular autophagy: A bridge to systematic wellness","authors":"Xiao-Han Zhou ,&nbsp;Ya-Xi Luo ,&nbsp;Xiu-Qing Yao","doi":"10.1016/j.jare.2024.12.036","DOIUrl":"10.1016/j.jare.2024.12.036","url":null,"abstract":"<div><h3>Background</h3><div>Exercise enhances health by supporting homeostasis, bolstering defenses, and aiding disease recovery. It activates autophagy, a conserved cellular process essential for maintaining balance, while dysregulated autophagy contributes to disease progression. Despite extensive research on exercise and autophagy independently, their interplay remains insufficiently understood.</div></div><div><h3>Aim of Review</h3><div>This review explores the molecular mechanisms of exercise-induced autophagy in various tissues, focusing on key transduction pathways. It examines how different types of exercise trigger specific autophagic responses, supporting cellular balance and addressing systemic dysfunctions. The review also highlights the signaling pathways involved, their roles in protecting organ function, reducing disease risk, and promoting longevity, offering a clear understanding of the link between exercise and autophagy.</div></div><div><h3>Key Scientific Concepts of Review</h3><div>Exercise-induced autophagy is governed by highly coordinated and dynamic pathways integrating direct and indirect mechanical forces and biochemical signals, linking physical activity to cellular and systemic health across multiple organ systems. Its activation is influenced by exercise modality, intensity, duration, and individual biological characteristics, including age, sex, and muscle fiber composition. Aerobic exercises primarily engage AMPK and mTOR pathways, supporting mitochondrial quality and cellular homeostasis. Anaerobic training activates PI3K/Akt signaling, modulating molecules like FOXO3a and Beclin1 to drive muscle autophagy and repair. In pathological contexts, exercise-induced autophagy enhances mitochondrial function, proteostasis, and tissue regeneration, benefiting conditions like sarcopenia, neurodegeneration, myocardial ischemia, metabolic disorders, and cancer. However, excessive exercise may lead to autophagic overactivation, leading to muscle atrophy or pathological cardiac remodeling. This underscores the critical need for balanced exercise regimens to maximize therapeutic efficacy while minimizing risks. Future research should prioritize identifying reliable biomarkers, optimizing exercise protocols, and integrating exercise with pharmacological strategies to enhance therapeutic outcomes.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 271-291"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Risk classification for non-cancer death in middle-aged cancer patients","authors":"Tianwang Guan ,&nbsp;Yanting Jiang ,&nbsp;Peinan Tu ,&nbsp;Baokui Ye ,&nbsp;Liangjia Zeng ,&nbsp;Zehao Luo ,&nbsp;Kaiyi Chi ,&nbsp;Haowen Liang ,&nbsp;Yuting Yang ,&nbsp;Jinqi Huang ,&nbsp;Binghua Zhang ,&nbsp;Rundong Tai ,&nbsp;Jujian Ye ,&nbsp;Zhilin Deng ,&nbsp;Yushen Ke ,&nbsp;Huiwan Chen ,&nbsp;Zhiling Zhang ,&nbsp;Zhigang Liu ,&nbsp;Caiwen Ou","doi":"10.1016/j.jare.2024.12.039","DOIUrl":"10.1016/j.jare.2024.12.039","url":null,"abstract":"<div><h3>Introduction</h3><div>Non-cancer events are important causes of competing mortality among cancer patients. However, the risk of non-cancer death and risk classification in middle-aged cancer patients is not clear. To comprehensively analyze the risk of non-cancer deaths in 24 different cancers among middle-aged patients.</div></div><div><h3>Methods</h3><div>Standardized mortality rate (SMR), absolute excess risk (AER), proportion of deaths, age-adjusted mortality rate (AAMR), and the competing model were used to assess the risk of non-cancer death in middle-aged cancer patients. A non-cancer death risk classification was developed for the 24 cancer types based on the competing risk of non-cancer death and the risk of non-cancer death (hazard ratio).</div></div><div><h3>Results</h3><div>A total of 1,082,030 middle-aged cancer patients of 24 cancer types was identified. The risk of non-cancer death was elevated in middle-aged cancer patients compared to the general middle-aged population (SMR = 3.37, 95 % CI 3.35–3.39, AER = 99.18). The cumulative mortality was higher for non-cancer causes compared to primary cancer in 15 cancer types. The AAMR for non-cancer causes declined from 2.3 % in 1975 to 1.4 % in 2017. A risk classification was developed to classify different cancers into 6 risk categories.</div></div><div><h3>Conclusion</h3><div>The risk of non-cancer death was elevated in middle-aged cancer patients and varied for different cancer types. A new risk classification system was developed to estimate the risk of non-cancer deaths in different cancers, and the 24 cancer types were classified into 6 distinct categories. These results highlight the necessity for risk stratification management for non-cancer death in middle-aged cancer patients.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 669-678"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting macrophages in cancer immunotherapy: Frontiers and challenges","authors":"Yu’e Liu ,&nbsp;Huabing Tan ,&nbsp;Jingyuan Dai ,&nbsp;Jianghua Lin ,&nbsp;Kaijun Zhao ,&nbsp;Haibo Hu ,&nbsp;Chunlong Zhong","doi":"10.1016/j.jare.2024.12.043","DOIUrl":"10.1016/j.jare.2024.12.043","url":null,"abstract":"<div><h3>Background</h3><div>Cancer immunotherapy has emerged as a groundbreaking approach in cancer treatment, primarily realized through the manipulation of immune cells, notably T cell adoption and immune checkpoint blockade. Nevertheless, the manipulation of T cells encounters formidable hurdles. Macrophages, serving as the pivotal link between innate and adaptive immunity, play crucial roles in phagocytosis, cytokine secretion, and antigen presentation. Consequently, macrophage-targeted therapies have garnered significant attention.</div></div><div><h3>Aim of review</h3><div>We aim to provide the most cutting-edge insights and future perspectives for macrophage-targeted therapies, fostering the development of novel and effective cancer treatments.</div></div><div><h3>Key scientific concepts of review</h3><div>To date, the forefront strategies for macrophage targeting encompass: altering their plasticity, harnessing CAR-macrophages, and targeting phagocytosis checkpoints. Macrophages are characterized by their remarkable diversity and plasticity, offering a unique therapeutic target. In this context, we critically analyze the innovative strategies aimed at transforming macrophages from their M2 (tumor-promoting) to M1 (tumor-suppressing) phenotype. Furthermore, we delve into the design principles, developmental progress, and advantages of CAR-macrophages. Additionally, we illuminate the challenges encountered in targeting phagocytosis checkpoints on macrophages and propose potential strategies to overcome these obstacles.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 695-713"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bacteroides uniformis ameliorates pro-inflammatory diet-exacerbated colitis by targeting endoplasmic reticulum stress-mediated ferroptosis","authors":"Caiguang Liu ,&nbsp;Linxin Liu ,&nbsp;Zhenyi Tian ,&nbsp;Shukai Zhan ,&nbsp;Yun Qiu ,&nbsp;Manying Li ,&nbsp;Tong Li ,&nbsp;Ren Mao ,&nbsp;Shenghong Zhang ,&nbsp;Minhu Chen ,&nbsp;Zhirong Zeng ,&nbsp;Xiaojun Zhuang","doi":"10.1016/j.jare.2024.11.025","DOIUrl":"10.1016/j.jare.2024.11.025","url":null,"abstract":"<div><h3>Introduction</h3><div>A pro-inflammatory diet is positively associated with the risk and progression of inflammatory bowel diseases (IBD). Recently, ferroptosis has been observed in patients with different dietary patterns-associated intestinal inflammation, while the mechanisms underlying the effects of a pro-inflammatory diet and whether it mediates ferroptosis are unknown.</div></div><div><h3>Objectives</h3><div>This study aims to elucidate the mechanisms underlying pro-inflammatory diet-mediated colitis and explore potential intervention strategies.</div></div><div><h3>Methods</h3><div>Mice were fed a dietary inflammatory index-based pro-inflammatory diet for 12 weeks. Subsequently, colitis was chemically induced using 2.5 % dextran sulfate sodium. The body weight, pathological score, immune response and mucosal barrier function were evaluated to assess intestinal inflammation. Intestine tissue transcriptomics, fecal microbiome analysis and serum metabolomics were applied to identify diet–microbe–host interactions. Additionally, the dietary inflammatory index (DII) scores and intestinal specimens of 32 patients with Crohn’s disease were evaluated. The biological functions of <em>Bacteroides uniformis</em> were observed <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Results</h3><div>Pro-inflammatory diet induces low-grade intestinal inflammation in mice and exacerbates colitis by activating glutathione peroxidase 4-associated ferroptosis in the endoplasmic reticulum stress-mediated pathway. These effects are reversed by ferrostatin-1 treatment. Additionally, the pro-inflammatory diet triggers colitis by modulating the gut microbiota and metabolites. Notably, supplementation with <em>B. uniformis</em> improves the pro-inflammatory diet-aggravated colitis by inhibiting endoplasmic reticulum stress-mediated ferroptosis. Moreover, <em>B. uniformis</em> is non-enterotoxigenic and non-enteroinvasive in co-cultures with intestinal epithelial cells.</div></div><div><h3>Conclusions</h3><div>Pro-inflammatory diet drives colitis by targeting endoplasmic reticulum stress-mediated ferroptosis, possibly in a gut microbiota-dependent manner. Pro-inflammatory diet restriction and microbial-based therapies may be effective strategies for preventing and treating IBD.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 481-499"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142670842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural small molecule hinokitone mitigates NASH fibrosis by targeting regulation of FXR-mediated hepatocyte apoptosis","authors":"Ze-Jiang Ma ,&nbsp;Ying-Kun Qiu ,&nbsp;Zhe-Wei Yu ,&nbsp;Tian-Tian Song ,&nbsp;Yi-Tong Hu ,&nbsp;An-Kang Peng ,&nbsp;Rong Qi","doi":"10.1016/j.jare.2024.12.016","DOIUrl":"10.1016/j.jare.2024.12.016","url":null,"abstract":"<div><h3>Introduction</h3><div>Liver fibrosis is the common fate of NASH and poses a major health threat with very limited pharmacological treatments.</div></div><div><h3>Objectives</h3><div>This study aims to investigate the preventive effect of hinokitone (HO), an isolated compound from <em>Agathis dammara</em>, on NASH fibrosis and its underlying mechanism.</div></div><div><h3>Methods</h3><div>To investigate the effect of HO on NASH fibrosis, C57BL/6 mice were either fed a high-fat diet (HFD) in conjunction with intraperitoneal injection of CCl₄ for 8 weeks or single CCl₄ for 14 days to establish mouse liver fibrosis model, and HO was administered by gavage simultaneously. To elucidate the underlying mechanisms, HepG2 cells were stimulated by palmitic acid (PA) or tumor necrosis factor α plus actinomycin-D (Act-D + TNFα) to induce hepatocyte apoptosis model. Furthermore, hepatocyte Farnesoid-X-receptor (FXR) specifically knocked out mice were established by the albumin-Cre-loxP recombination enzyme system to ascertain the role of FXR in the anti-NASH fibrosis effects of HO.</div></div><div><h3>Results</h3><div>The results showed that HO presented dose-dependent anti-liver fibrosis efficacy in NASH mice induced by HFD + CCl₄ and CCl₄-induced mouse liver fibrosis. Cellularly, HO significantly inhibited PA-induced lipotoxic apoptosis and Act-D + TNFα-induced exogenous apoptosis in hepatocytes, which in turn prevented HSC activation. Mechanistically, bioinformatics analysis and surface plasmon resonance assay had identified hepatocyte FXR as a target of HO. Specifically, HO directly bound to FXR and upregulated its protein level by inhibiting proteasomal degradation. In turn, HO attenuated hepatocyte lipid deposition through upregulating the FXR’s downstream target genes <em>SHP</em> and <em>CES1</em>, and reduced cleaved-CASP8 level, thereby inhibiting hepatocyte apoptosis. Furthermore, HO lost its function in the inhibition of hepatocyte apoptosis and liver fibrosis when knockout hepatocyte FXR.</div></div><div><h3>Conclusion</h3><div>In conclusion, HO has an inhibitory effect on NASH fibrosis. This effect is mediated by targeting upregulation of hepatocyte FXR, which in turn attenuates hepatocyte apoptosis and thus indirectly inhibits the activation of HSCs.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 553-568"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics approach reveals TGF-β signaling-driven senescence in periodontium stem cells","authors":"Bo Li ,&nbsp;Wei Li ,&nbsp;Yueqi Liao ,&nbsp;Zhijie Weng ,&nbsp;Yafei Chen ,&nbsp;Takehito Ouchi ,&nbsp;Yi Fan ,&nbsp;Zhihe Zhao ,&nbsp;Longjiang Li","doi":"10.1016/j.jare.2024.12.037","DOIUrl":"10.1016/j.jare.2024.12.037","url":null,"abstract":"<div><h3>Introduction</h3><div>The periodontal ligament (PDL), a dynamic connective tissue that anchors teeth to the alveolar bone, enables tooth retention and facilitates continuous turnover. The integrity of the periodontium is maintained by periodontal ligament stem cells (PDLSCs), whose dysfunction and senescence with age can disrupt tissue homeostasis, hinder injury repair, and lead to tooth loss, ultimately impacting overall health. Transforming growth factor-β1 (TGF-β1) is known for its regenerative properties and as a functional paracrine factor in stem cell therapy, but its precise role in modulating PDLSC activity remains controversial and poorly understood.</div></div><div><h3>Objectives</h3><div>This study aims to clarify the role of TGF-β1 in PDLSC senescence and identify the underlying molecular mechanisms, thereby advancing our understanding of age-related periodontal diseases and informing the development of targeted therapeutic strategies.</div></div><div><h3>Methods</h3><div>We employed spatial transcriptomics to map <em>Tgfb1</em> mRNA expression in murine jawbone tissues, focusing on its distribution in the periodontium. Pseudotime analysis was performed to assess expression patterns and infer temporal dynamics. Human PDLSCs were used as a model to investigate the effects of TGF-β1 signaling, with assays conducted to examine DNA methylation, senescence phenotypes, cell cycle arrest, and underlying signaling pathways.</div></div><div><h3>Results</h3><div>Spatial transcriptomic profiling revealed enriched <em>Tgfb1</em> expression in the periodontium, with upregulation tendencies. In human PDLSCs, TGF-β1 treatment induced a senescent phenotype marked by G2 phase cell cycle arrest and increased reactive oxygen species (ROS) accumulation. Mechanistically, TGF-β1 triggered ROS production through DNA methylation-mediated silencing of <em>PRKAG2</em>, a gene encoding AMPKγ2, resulting in ROS accumulation, DNA damage, and ATM signaling activation. Importantly, inhibition of ROS with N-acetyl-l-cysteine (NAC) or reversal of <em>PRKAG2</em> epigenetic silencing with decitabine mitigated PDLSC senescence by suppressing ATM signaling.</div></div><div><h3>Conclusion</h3><div>Our work presents the first spatially resolved transcriptomic landscape of murine jawbone tissues and uncovers DNA methylation as a crucial mechanism underlying TGF-β1-induced PDLSC senescence. These findings illuminate a previously unrecognized link between TGF-β1 signaling, ROS production, and epigenetic regulation, offering promising avenues for developing stem cell-based therapies to attenuate age-related periodontal diseases and improve systemic health.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 387-403"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142901852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated EBF2 in mouse but not pig drives the progressive brown fat lineage specification via chromatin activation","authors":"Yinlong Liao ,&nbsp;Zhelun Peng ,&nbsp;Shanshan Fu ,&nbsp;Yao Hua ,&nbsp;Wenzhe Luo ,&nbsp;Ruige Liu ,&nbsp;Yingjin Chen ,&nbsp;Wei Gu ,&nbsp;Pengxiang Zhao ,&nbsp;Jianguo Zhao ,&nbsp;Yanfang Wang ,&nbsp;Heng Wang","doi":"10.1016/j.jare.2024.12.046","DOIUrl":"10.1016/j.jare.2024.12.046","url":null,"abstract":"<div><div>Brown adipose tissue (BAT) is responsible for non-shivering thermogenesis, but it is absent in some mammals, including pigs. During development, BAT progenitors are derived from paired box 7 (Pax7)-expressing somitic mesodermal stem cells, which also give rise to skeletal muscle. However, the intrinsic mechanisms underlying the fate decisions between brown fat and muscle progenitors remain elusive across species. In this study, we analyzed the dynamics of chromatin landscape during the segregation and specification of brown fat and muscle lineages from Pax7⁺ multipotent mesodermal stem cells, aiming to uncover epigenetic factors that drive de novo BAT formation. Notably, myogenic progenitors were specified at embryonic day (E) 12.5, exhibiting high levels of H3K4me3 and low H3K27me3 at muscle-related genes. In contrast, the specification of the BAT lineage occurred much later, with coordinated step-wise depositions of histone modifications at BAT-associated genes from E10.5 to E14.5. We identified the transcription factor early B-cell factor 2 (EBF2) as a key driver of the progressive specification of brown fat lineage and the simultaneous deviation away from the muscle lineage. Mechanistically, EBF2 interacts with transcriptional co-activators CREB binding protein/ E1A-binding protein p300 (CBP/P300) to induce H3K27ac deposition and chromatin activation at BAT-associated genes to promote brown adipogenesis. Both mouse and pig EBF2 could potently stimulate adipogenesis in unspecified multipotent mesodermal stem cells. However, in pigs, EBF2 expression was depleted during the critical lineage specification time window, thus preventing the embryonic formation and development of porcine BAT. Hence, the elevation of EBF2 in mice, but not in pigs, promote chromatin activation to drive the progressive specification of brown fat lineage.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 327-344"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142888956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}