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Natural small molecule hinokitone mitigates NASH fibrosis by targeting regulation of FXR-mediated hepatocyte apoptosis 天然小分子扁桃素通过靶向调节fxr介导的肝细胞凋亡减轻NASH纤维化
IF 13 1区 综合性期刊
Journal of Advanced Research Pub Date : 2025-10-01 DOI: 10.1016/j.jare.2024.12.016
Ze-Jiang Ma , Ying-Kun Qiu , Zhe-Wei Yu , Tian-Tian Song , Yi-Tong Hu , An-Kang Peng , Rong Qi
{"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 CCl<sub>4</sub> for 8 weeks or single CCl<sub>4</sub> 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 + CCl<sub>4</sub> and CCl<sub>4</sub>-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}
引用次数: 0
Multi-omics approach reveals TGF-β signaling-driven senescence in periodontium stem cells 多组学方法揭示TGF-β信号驱动的牙周组织干细胞衰老
IF 13 1区 综合性期刊
Journal of Advanced Research Pub Date : 2025-10-01 DOI: 10.1016/j.jare.2024.12.037
Bo Li , Wei Li , Yueqi Liao , Zhijie Weng , Yafei Chen , Takehito Ouchi , Yi Fan , Zhihe Zhao , Longjiang Li
{"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}
引用次数: 0
Elevated EBF2 in mouse but not pig drives the progressive brown fat lineage specification via chromatin activation 小鼠(而非猪)中EBF2的升高通过染色质激活驱动褐色脂肪谱系的进行性规范
IF 13 1区 综合性期刊
Journal of Advanced Research Pub Date : 2025-10-01 DOI: 10.1016/j.jare.2024.12.046
Yinlong Liao , Zhelun Peng , Shanshan Fu , Yao Hua , Wenzhe Luo , Ruige Liu , Yingjin Chen , Wei Gu , Pengxiang Zhao , Jianguo Zhao , Yanfang Wang , Heng Wang
{"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<sup>+</sup> 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}
引用次数: 0
Targeting APJ drives BNIP3-PINK1-PARKIN induced mitophagy and improves systemic inflammatory bone loss 靶向APJ驱动bniip3 - pink1 - parkin诱导的线粒体自噬,改善全身性炎症性骨丢失
IF 13 1区 综合性期刊
Journal of Advanced Research Pub Date : 2025-10-01 DOI: 10.1016/j.jare.2024.12.033
Wentao Wang , Qing Wang , Wenming Li , Hao Xu , Xiaolong Liang , Wei Wang , Ning Li , Huilin Yang , Yaozeng Xu , Jiaxiang Bai , Shuli Yang , Dechun Geng
{"title":"Targeting APJ drives BNIP3-PINK1-PARKIN induced mitophagy and improves systemic inflammatory bone loss","authors":"Wentao Wang ,&nbsp;Qing Wang ,&nbsp;Wenming Li ,&nbsp;Hao Xu ,&nbsp;Xiaolong Liang ,&nbsp;Wei Wang ,&nbsp;Ning Li ,&nbsp;Huilin Yang ,&nbsp;Yaozeng Xu ,&nbsp;Jiaxiang Bai ,&nbsp;Shuli Yang ,&nbsp;Dechun Geng","doi":"10.1016/j.jare.2024.12.033","DOIUrl":"10.1016/j.jare.2024.12.033","url":null,"abstract":"<div><h3>Introduction</h3><div>Inflammatory diseases, such as diabetes mellitus, rheumatoid arthritis, and inflammatory bowel disease, lead to systemic immune microenvironment disturbances, contributing to bone loss, yet the mechanisms by which specific receptors regulate this process in inflammatory bone loss remain poorly understood. As a G-protein-coupled receptor, the Apelin receptor plays a crucial role in the regulation of inflammation and immune microenvironment. However, the precise mechanisms governing its role in inflammatory bone loss remain incompletely understood.</div></div><div><h3>Objective</h3><div>This study aims to investigate how APJ regulates macrophage polarization to mitigate inflammatory bone loss.</div></div><div><h3>Methods</h3><div>Lipopolysaccharide induced systemic inflammatory bone loss model in mice was used to explore the relationship between bone loss and osteoclast activation, macrophage polarization and APJ. In vitro studies, Bone marrow derived macrophages and siRNA were used to elucidate the regulatory influence of APJ on the immune microenvironment and osteoclast differentiation, while high-throughput sequencing is leveraged to uncover the underlying mechanisms through which APJ modulates macrophage polarization.</div></div><div><h3>Results</h3><div>Our study established a link between APJ and macrophage M1 polarization in systemic inflammatory bone loss mice. The activation of APJ effectively mitigated M1 polarization in macrophages, suppressed excessive osteoclast activation, and alleviated systemic inflammatory bone loss. In vitro high-throughput sequencing analysis revealed that APJ modulates macrophage polarization, linking to mitochondrial autophagy and the NOD-like receptor signaling pathway and the involvement of the AMPK and MAPK signaling pathways in signal transduction after APJ activation was also suggested. Subsequent experiments substantiated that APJ predominantly enhances mitophagy and diminishes the accumulation of reactive oxygen species by regulating the AMPK/BNIP3/PINK1/PARKIN axis, thereby suppressing the activation of macrophage M1 polarization and osteoclastogenesis.</div></div><div><h3>Conclusion</h3><div>This study elucidated the underlying mechanism by which APJ modulates macrophage polarization, thereby proposing a new therapeutic target for addressing inflammatory bone loss.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 655-668"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142884684","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}
引用次数: 0
Absence of gut microbiota alleviates iron overload-induced colitis by modulating ferroptosis in mice 肠道菌群缺失通过调节小鼠铁下垂减轻铁超载诱导的结肠炎
IF 13 1区 综合性期刊
Journal of Advanced Research Pub Date : 2025-10-01 DOI: 10.1016/j.jare.2024.12.030
Ke Gu , Aimin Wu , Chen Liu , Bing Yu , Jun He , Xin Lai , Junzhou Chen , Yuheng Luo , Hui Yan , Ping Zheng , Junqiu Luo , Junning Pu , Quyuan Wang , Huifen Wang , Daiwen Chen
{"title":"Absence of gut microbiota alleviates iron overload-induced colitis by modulating ferroptosis in mice","authors":"Ke Gu ,&nbsp;Aimin Wu ,&nbsp;Chen Liu ,&nbsp;Bing Yu ,&nbsp;Jun He ,&nbsp;Xin Lai ,&nbsp;Junzhou Chen ,&nbsp;Yuheng Luo ,&nbsp;Hui Yan ,&nbsp;Ping Zheng ,&nbsp;Junqiu Luo ,&nbsp;Junning Pu ,&nbsp;Quyuan Wang ,&nbsp;Huifen Wang ,&nbsp;Daiwen Chen","doi":"10.1016/j.jare.2024.12.030","DOIUrl":"10.1016/j.jare.2024.12.030","url":null,"abstract":"<div><h3>Introduction</h3><div>Iron overload disrupts gut microbiota and induces ferroptosis, contributing to colitis. However, whether gut microbiota directly drives iron overload-induced colitis and its underlying mechanism remain unclear.</div></div><div><h3>Objectives</h3><div>The study aimed to explore whether gut microbiota can directly regulate iron overload-induced colitis and its underling mechanism.</div></div><div><h3>Methods</h3><div>Male C57BL/6N mice were fed with ferrous sulfate to establish an iron overload model. Antibiotics and dextran sulfate sodium salt (DSS) were used to create germ-free and colitis models, respectively.</div></div><div><h3>Results</h3><div>Results showed that iron overload caused disruption of systemic iron homeostasis via activating pro-inflammation response, which caused induction of ferroptosis and eventually resulted in colitis in mice. Notably, iron overload inhibited System Xc- and activated the nuclear factor E2-related factor 2/heme oxygenase-1 pathway, driving ferroptosis and colitis progression. Similar results were observed in mouse colon epithelial cells, which were treated with high doses ferric ammonium citrate. Additionally, iron overload exacerbated DSS-induced colitis by activating the ferroptosis and increasing harmful bacteria (e.g., <em>Mucispirillum</em>) abundance. Interestingly, eliminating gut microbiota attenuated iron overload-induced colitis, without affecting systemic inflammation through inhibiting ferroptosis of mice. Depletion of the gut microbiota partially mitigated the exacerbating effect of iron overload on DSS-induced colitis through inhibiting ferroptosis of mice.</div></div><div><h3>Conclusion</h3><div>Iron overload activates ferroptosis in colonic cells, increases the relative abundance of harmful bacteria, and exacerbates DSS-induced colitis in mice. Iron overload exacerbates DSS-induced ferroptosis and colitis in a microbiota-dependent manner. Targeting gut microbiota may offer new strategies for managing iron overload-induced colitis.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 233-250"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867557","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}
引用次数: 0
The role of trehalose metabolism in plant stress tolerance 海藻糖代谢在植物抗逆性中的作用
IF 13 1区 综合性期刊
Journal of Advanced Research Pub Date : 2025-10-01 DOI: 10.1016/j.jare.2024.12.025
Tong-Ju Eh , Yaxuan Jiang , Mingquan Jiang , Jianxin Li , Pei Lei , Ximei Ji , Hyon-Il Kim , Xiyang Zhao , Fanjuan Meng
{"title":"The role of trehalose metabolism in plant stress tolerance","authors":"Tong-Ju Eh ,&nbsp;Yaxuan Jiang ,&nbsp;Mingquan Jiang ,&nbsp;Jianxin Li ,&nbsp;Pei Lei ,&nbsp;Ximei Ji ,&nbsp;Hyon-Il Kim ,&nbsp;Xiyang Zhao ,&nbsp;Fanjuan Meng","doi":"10.1016/j.jare.2024.12.025","DOIUrl":"10.1016/j.jare.2024.12.025","url":null,"abstract":"<div><h3>Background</h3><div>Trehalose is a nonreducing disaccharide containing two glucose molecules linked through an α,α-1,1-glycosidic bond. This unique chemical structure causes trehalose levels to fluctuate significantly in plants under stress, where it functions as an osmoprotectant, enhancing plant resistance to stress. Previous studies have confirmed that the trehalose synthesis pathway is widely conserved across most plants. However, the protective role of trehalose is limited only to organelles or tissues where the concentration is sufficiently high.</div></div><div><h3>Aim of review</h3><div>In this review, we summarize previous reports on improving plant stress tolerance (drought, cold, heat, salt, pathogen, etc.) by applying trehalose-6-phosphate (T6P) or trehalose and manipulating the expression of trehalose metabolism-related genes. The molecular mechanisms underlying T6P, trehalose, and their related genes that regulate plant stress resistance are reviewed. More progressive studies on the spatiotemporal control of trehalose metabolism will provide a novel tool that allows for the simultaneous enhancement of crop yield and stress tolerance.</div></div><div><h3>Key scientific concepts of review</h3><div>We introduce the history of trehalose and discuss the possibility of trehalose and its metabolity-related genes binding to T6P to participate in stress response through unknown signaling pathways. In addition, the effects of trehalose metabolism regulation on plant growth and stress resistance were reviewed, and the molecular mechanism was fully discussed. In particular, we came up with new insights that the molecular mechanism of trehalose metabolism to enhance plant stress resistance in the future and we propose the need to use biotechnology methods to cultivate crops with stress resistance and high yield potential.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 57-72"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857865","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}
引用次数: 0
FTO activates PD-L1 promotes immunosuppression in breast cancer via the m6A/YTHDF3/PDK1 axis under hypoxic conditions 缺氧条件下,FTO通过m6A/YTHDF3/PDK1轴激活PD-L1促进乳腺癌的免疫抑制
IF 13 1区 综合性期刊
Journal of Advanced Research Pub Date : 2025-10-01 DOI: 10.1016/j.jare.2024.12.026
Siyu Wang , Xingda Zhang , Quanrun Chen , Hao Wu , Shihan Cao , Shilu Zhao , Guozheng Li , Jianyu Wang , Yajie Gong , Xinheng Wang , Da Pang , Song Gao
{"title":"FTO activates PD-L1 promotes immunosuppression in breast cancer via the m6A/YTHDF3/PDK1 axis under hypoxic conditions","authors":"Siyu Wang ,&nbsp;Xingda Zhang ,&nbsp;Quanrun Chen ,&nbsp;Hao Wu ,&nbsp;Shihan Cao ,&nbsp;Shilu Zhao ,&nbsp;Guozheng Li ,&nbsp;Jianyu Wang ,&nbsp;Yajie Gong ,&nbsp;Xinheng Wang ,&nbsp;Da Pang ,&nbsp;Song Gao","doi":"10.1016/j.jare.2024.12.026","DOIUrl":"10.1016/j.jare.2024.12.026","url":null,"abstract":"<div><h3>Introduction</h3><div>Altered epigenetic reprogramming enables breast cancer cells to adapt to hypoxic stress. Hypoxic microenvironment can alter immune cell infiltration and function, limiting the effectiveness of immunotherapy.</div></div><div><h3>Objectives</h3><div>The study aimed to identify how fat mass and obesity-associated protein (FTO) helps breast cancer cells cope with the hypoxic microenvironment and the mechanisms behind breast cancer cell resistance to tumor immunity.</div></div><div><h3>Methods</h3><div>Clinical samples were utilized to analyze the impact of FTO on breast cancer progression and the effect of programmed cell death protein 1/ programmed cell death 1 ligand 1(PD-1/PD-L1) immune checkpoint inhibitor treatment. Utilized MeRIP-seq and mRNA-seq to analyze the downstream genes regulated by FTO under hypoxia. Methylation modification regulation of PDK1 by FTO was clarified using RIP. Then mouse models were utilized to analyze the efficacy of inhibiting FTO and 3-Phosphoinositide-dependent protein kinase 1(PDK1) in combination with PD-1/PD-L1 immune checkpoint inhibitor treatment.</div></div><div><h3>Result</h3><div>N6-Methyladenosine(m<sup>6</sup>A) demethylase FTO was transcriptionally activated by hypoxia inducible factor 1α(HIF-1α). PDK1 was identified as a potential target of FTO under hypoxic conditions through high-throughput sequencing. Mechanistically, overexpression of FTO decreases m<sup>6</sup>A modification sites on PDK1 mRNA, preventing YTH domain family 3(YTHDF3) from recognizing and binding to these sites, thereby inhibiting the degradation of PDK1 mRNA. Overexpression of PDK1 activates the AKT/STAT3 pathway, leading to enhanced PD-L1 expression. Targeting the FTO and PDK1-AKT pathways with FB23 and BX-912 inhibit breast cancer growth, enhance cytotoxic T lymphocyte (CTL) activity, and enhance the effectiveness of the PD-1/PD-L1 checkpoint inhibitor Atezolizumab.</div></div><div><h3>Conclusion</h3><div>This study reveals that HIF-1α promotes FTO transcription under hypoxic conditions, thereby increasing PD-L1 expression through the PDK1/AKT/STAT3 axis. Inhibition of FTO and PDK1 under hypoxic conditions could serve as a promising immunotherapeutic strategy for breast cancer.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 191-206"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142841526","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}
引用次数: 0
Advances in statin adverse reactions and the potential mechanisms: A systematic review 他汀类药物不良反应及其潜在机制的研究进展:综述
IF 13 1区 综合性期刊
Journal of Advanced Research Pub Date : 2025-10-01 DOI: 10.1016/j.jare.2024.12.020
Weiwei Zeng , Huan Deng , Yuning Luo , Shilong Zhong , Min Huang , Brian Tomlinson
{"title":"Advances in statin adverse reactions and the potential mechanisms: A systematic review","authors":"Weiwei Zeng ,&nbsp;Huan Deng ,&nbsp;Yuning Luo ,&nbsp;Shilong Zhong ,&nbsp;Min Huang ,&nbsp;Brian Tomlinson","doi":"10.1016/j.jare.2024.12.020","DOIUrl":"10.1016/j.jare.2024.12.020","url":null,"abstract":"<div><div><strong>Background:</strong> Elevated low-density lipoprotein (LDL) cholesterol is a major risk factor for cardiovascular disease. Statins are the cornerstone of preventing and treating cardiovascular disease and can reduce LDL cholesterol by more than 60%. Although statins have high tolerability and safety, as the number of users increases, their adverse reactions in the liver, kidneys, skeletal muscles, and their potential to induce diabetes have also received widespread attention.</div><div>Aim <strong>of review:</strong> How to maximize the lipid-lowering effect of statins, reduce the incidence of adverse reactions, promote the rational application of statins in the clinic, and improve the risk–benefit level, in order to benefit more cardiovascular patients and provide reference for the related basic research of statins.</div><div><strong>Key scientific concepts of review:</strong> This article provides a comprehensive review of the clinical manifestations of statin-related adverse reactions (associated myopathy, hepatotoxicity, nephrotoxicity, glycemic effects, central nervous system, hemorrhagic stroke, etc.), risk factors for triggering adverse reactions, statin interactions with other drugs (food), potential etiopathological mechanisms and common interventions in the clinic. Genetic diversity is strongly associated with statin adverse effects, and thus, in the future genetic testing may also be key to mitigating statin adverse effects.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 781-797"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142820952","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}
引用次数: 0
Bio-friendly multi-stimuli responsive α-CD polymer-gated mesoporous carbon nanoherbicides for enhanced paraquat delivery 生物友好型多刺激响应α-CD聚合物门控介孔碳纳米除草剂增强百草草的递送
IF 13 1区 综合性期刊
Journal of Advanced Research Pub Date : 2025-10-01 DOI: 10.1016/j.jare.2024.12.005
Jiangtao Dong , Guoquan Wang , Xiaona Li , Aohui Han , Wanpeng Zhang , Yuhang Yue , Yue Yang , Yishan Wang , Bowen Yuan , Jiahui Wang , Yuhui Peng , Runqiang Liu , Si Chen , Xuezhong Du
{"title":"Bio-friendly multi-stimuli responsive α-CD polymer-gated mesoporous carbon nanoherbicides for enhanced paraquat delivery","authors":"Jiangtao Dong ,&nbsp;Guoquan Wang ,&nbsp;Xiaona Li ,&nbsp;Aohui Han ,&nbsp;Wanpeng Zhang ,&nbsp;Yuhang Yue ,&nbsp;Yue Yang ,&nbsp;Yishan Wang ,&nbsp;Bowen Yuan ,&nbsp;Jiahui Wang ,&nbsp;Yuhui Peng ,&nbsp;Runqiang Liu ,&nbsp;Si Chen ,&nbsp;Xuezhong Du","doi":"10.1016/j.jare.2024.12.005","DOIUrl":"10.1016/j.jare.2024.12.005","url":null,"abstract":"<div><h3>Introduction</h3><div>Weeds seriously affect crop yield in global agricultural production. Paraquat (PQ), as one of low cost and highly effective herbicide, is forbidden or severely restricted in production and sales owing to its lethal toxicity to humans. Creating an efficient and bio-friendly PQ formulation is crucial to facilitate the open use of PQ in world’s agriculture.</div></div><div><h3>Objectives</h3><div>This study aims to construct one intelligent and bio-friendly mesoporous carbon nanoparticles (MCN) nanoherbicides coated with α-CD polymer (CDP) gatekeepers.</div></div><div><h3>Methods</h3><div>MCN was prepared through the low-concentration hydrothermal way, calcined and carbonized. PEG stalks were immobilized on MCN surface by amidation reaction. The PQ was trapped in the MCN pores via physical diffusion adsorption and the robust π–π effects between electron-deficient PQ and electron-rich MCN. CDP gatekeepers were fastened via host–guest effects between the chamber of α-CD units and PEG stalks.</div></div><div><h3>Results</h3><div>The PQ-loaded MCN-PEG@CDP nanoherbicides integrated with multi-stimuli responses to amylase, elevated temperature under sunlight, and competitors at leaf interface to control the PQ release for efficient weed control, while appeared low PQ leakage under the simulated human gastric or intestinal conditions, low cytotoxicity to human normal cells <em>in vitro</em>, and high mouse survival rate <em>in vivo</em>. Even through the nanoherbicides inevitably contact with water or intake by beneficial insects, they appear good biosafety on zebrafish (<em>D. rerio</em>) and honeybees (<em>Apis mellifera L</em>.).</div></div><div><h3>Conclusion</h3><div>The as-prepared nanoherbicides have high herbicidal efficacy and low risks to non-target species, and could promote the open use of PQ in agriculture.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 1-16"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142809721","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}
引用次数: 0
Interleukin-10 deficiency suppresses colorectal cancer metastasis by enriching gut Parabacteroides distasonis 白细胞介素-10 缺乏可通过富集肠道副杆菌抑制结直肠癌转移
IF 13 1区 综合性期刊
Journal of Advanced Research Pub Date : 2025-10-01 DOI: 10.1016/j.jare.2024.11.024
Jing Yu , Lili Feng , Zhanhao Luo , Jingyi Yang , Qiang Zhang , Chen Liu , Dayi Liang , Yanchun Xie , Hongmin Li , Junli Gong , Zhen He , Ping Lan
{"title":"Interleukin-10 deficiency suppresses colorectal cancer metastasis by enriching gut Parabacteroides distasonis","authors":"Jing Yu ,&nbsp;Lili Feng ,&nbsp;Zhanhao Luo ,&nbsp;Jingyi Yang ,&nbsp;Qiang Zhang ,&nbsp;Chen Liu ,&nbsp;Dayi Liang ,&nbsp;Yanchun Xie ,&nbsp;Hongmin Li ,&nbsp;Junli Gong ,&nbsp;Zhen He ,&nbsp;Ping Lan","doi":"10.1016/j.jare.2024.11.024","DOIUrl":"10.1016/j.jare.2024.11.024","url":null,"abstract":"<div><h3>Introduction</h3><div>The intricate interplay of interleukin-10 (IL-10) and gut microbiota influences tumor development and progression, yet the impacts on colorectal cancer (CRC) metastasis remain incompletely understood.</div></div><div><h3>Methods</h3><div>The impact of <em>Il10</em> deficiency on CRC metastasis was first evaluated in CRC metastasis tumor samples and mouse model. Antibiotic sterilization and fecal microbiota transplantation (FMT) experiment were used to assess the role of gut microbiota in IL-10 mediated CRC metastasis, and full-length 16S rDNA sequencing analysis further identified the potential target bacteria influencing CRC metastasis. The inhibitory effect of <em>Parabacteroides distasonis</em> (<em>P. distasonis</em>) on CRC metastasis was evaluated by oral administration in mice. Key metabolites involved in <em>P. distasonis</em> inhibition of CRC metastasis was identified by widely-targeted metabolome analysis and validated both <em>in vivo</em> and <em>in vitro</em>. The underlying mechanisms of P-hydroxyphenyl acetic acid (4-HPAA) inhibiting CRC metastasis was investigated via RNA-sequencing and validated in cellular experiments.</div></div><div><h3>Results</h3><div>We revealed that serum IL-10 levels were markedly elevated in metastatic CRC patients compared to non-metastatic cases. In parallel, <em>Il10</em>-deficiency (<em>Il10<sup>−/−</sup></em>) in mice resulted in decreased CRC metastasis in a gut microbiota-dependent manner. Mechanistically, <em>Il10<sup>−/−</sup></em> mice reshaped gut microbiota composition, notably enriching <em>P. distasonis</em>. The enriched <em>P. distasonis</em> produced 4-HPAA, which activated the aryl hydrocarbon receptor (AHR) and subsequently inhibited the expression of <em>VEGFA</em>, a typical oncogene, thereby sequentially suppressing CRC metastasis. Importantly, engineered bacteria capable of producing 4-HPAA effectively hindered CRC metastasis. Furthermore, AHR depletion significantly disrupted the 4-HPAA-induced reduction in CRC cell migration and the inhibition of metastasis in both <em>in vitro</em> and <em>in vivo</em> lung metastasis mouse models.</div></div><div><h3>Conclusions</h3><div>These findings demonstrate the significance of IL-10 deficiency in suppressing CRC metastasis through the 4-HPPA-AHR-<em>VEGFA</em> axis mediated by gut <em>P. distasonis</em>, suggesting that <em>P. distasonis</em> or 4-HPAA supplementation could offer a promising therapeutic strategy for CRC metastasis prevention.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"76 ","pages":"Pages 467-479"},"PeriodicalIF":13.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673783","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}
引用次数: 0
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