Journal of Advanced Research最新文献

{"title":"Intestinal T-cell migration: unraveling mechanisms and therapeutic implications","authors":"Yadong Sun,Yuqing Liu,Lingxiang Xie,Lemei Zhu,Weijun Peng","doi":"10.1016/j.jare.2026.10.019","DOIUrl":"https://doi.org/10.1016/j.jare.2026.10.019","url":null,"abstract":"","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"8 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149150572","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":"Boosting luteolin bioavailability via P-glycoprotein efflux inhibition: a self-microemulsifying drug delivery systems","authors":"Yimei Zheng,&nbsp;Boyu Chen,&nbsp;Xuanxiang Huang,&nbsp;Chao Ai,&nbsp;Hui Teng,&nbsp;Lei Chen","doi":"10.1016/j.jare.2026.01.030","DOIUrl":"10.1016/j.jare.2026.01.030","url":null,"abstract":"<div><h3>Introduction</h3><div>The poor bioavailability of luteolin, a potent flavonoid with antioxidant and anti-inflammatory properties, hinders its therapeutic potential. The primary barriers to its absorption are its low solubility and active efflux by P-glycoprotein (P-gp) in the gastrointestinal tract.</div></div><div><h3>Objectives</h3><div>To overcome these absorption barriers, we developed a functional self-microemulsifying drug delivery system (SME) incorporating D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), aiming to simultaneously enhance solubility, inhibit P-gp efflux, and improve the oral bioavailability and therapeutic efficacy of luteolin.</div></div><div><h3>Methods</h3><div>A TPGS-based luteolin-SME was prepared via self-assembly and characterized for particle size, stability, release profile, and antioxidant capacity. Cellular absorption mechanisms, permeability, and P-gp inhibition were evaluated using Caco-2 monolayers and molecular docking. Pharmacokinetics and biodistribution were assessed in rats, and therapeutic efficacy was examined in a lipopolysaccharide-induced inflammation model.</div></div><div><h3>Results</h3><div>The optimized luteolin-SME formed uniform nanodroplets (&lt;50 nm) with high stability and achieved a 4.3-fold higher cumulative release compared to free luteolin. In Caco-2 cells, the formulation significantly enhanced cellular uptake and permeability, primarily via clathrin- and caveolae-mediated endocytosis, and effectively inhibited P-gp efflux. Pharmacokinetically, luteolin-SME provided a 29-fold increase in relative bioavailability (AUC 247.729 vs. 8.628 mg/L·h) and a 16-fold higher Cmax (27.546 mg/L) over free luteolin. In the lipopolysaccharide-induced inflammation model, luteolin-SME markedly attenuated oxidative stress, reducing the TNF-α, IL-6, and IL-1β levels by approximately 37%, 26%, and 39%, respectively.</div></div><div><h3>Conclusion</h3><div>The TPGS-functionalized SME effectively overcame the major absorption barriers of luteolin by integrating nanocarrier-enhanced solubilization with active P-gp inhibition. This dual strategy resulted in unprecedented oral bioavailability enhancement and potent efficacy. Our study establishes a robust and clinically promising delivery platform for luteolin and other poorly soluble, efflux-limited bioactive compounds, offering a practical approach to enhance oral therapy for inflammation-related diseases.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 1095-1117"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Illustrating the functional heterogeneity of M-MDSCs to predict sepsis outcomes","authors":"Guoxing Tang,&nbsp;Wenjin Xing,&nbsp;Lin Zhu,&nbsp;Yuting Lu,&nbsp;Kaishan Jiang,&nbsp;Shiji Wu,&nbsp;Ziyong Sun,&nbsp;Hongyan Hou,&nbsp;Liming Cheng,&nbsp;Fan He,&nbsp;Feng Wang","doi":"10.1016/j.jare.2026.01.008","DOIUrl":"10.1016/j.jare.2026.01.008","url":null,"abstract":"<div><h3>Introduction</h3><div>Sepsis remains one of the leading causes of death worldwide. Monocytes play a pivotal role in sepsis due to their dual role in both pro-inflammation and immunosuppression. However, the phenotypic markers and developmental characteristics of immunosuppressive monocytic myeloid-derived suppressor cells (M-MDSCs) in sepsis remain largely unknown.</div></div><div><h3>Objectives</h3><div>This study aimed to investigate the functional heterogeneity of M-MDSCs in sepsis.</div></div><div><h3>Methods</h3><div>The frequency of M-MDSCs was assessed for the prognosis of sepsis. Single-cell RNA sequencing was conducted on purified HLA-DR^highCD14⁺ and HLA-DR^lowCD14⁺ monocytes, respectively, from patients with sepsis to study their heterogeneity.</div></div><div><h3>Results</h3><div>We find that the frequency of M-MDSCs, as defined by classical markers, has limited value in the prognosis of sepsis due to their broad heterogeneity. Based on scRNA-seq analysis, M-MDSCs in sepsis are established as HLA-DR^lowCD14⁺ monocytes, which display high expression of RETN and low expression of HLA-DPB1. We further segregate M-MDSCs into five subsets: IL1R2_M-MDSC, THBS1_M-MDSC, S100A_M-MDSC, IFN-sti_M-MDSC, and PPBP_M-MDSC, with the first three subsets accounting for the majority of the population. Pro-inflammatory S100A_M-MDSC dominates early-stage population and is characterized by high expression of S100A. Middle-stage IL1R2_M-MDSC exhibits cytokine production, while THBS1_M-MDSC is associated with TGF-β signaling, revealing concurrent pro-inflammatory and immunosuppressive functions. In the late stage, both THBS1_M-MDSC and IL1R2_M-MDSC display immunosuppressive functions. Furthermore, our data suggest a metabolic shift from oxidative phosphorylation to fatty acid and amino acid biosynthesis as pro-inflammatory monocytes transition into immunosuppressive M-MDSCs. VSIG4, a novel functional marker of immunosuppressive M-MDSCs, is specifically expressed in THBS1_M-MDSC. Subsequently, our preliminary results suggest that the combined detection of surface VSIG4 and IL1R2 on HLA-DR^lowCD14⁺ monocytes shows potential for predicting sepsis outcomes.</div></div><div><h3>Conclusion</h3><div>This study illuminates the characteristics of M-MDSCs in sepsis, providing a new direction for disease prognosis.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 807-824"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fructooligosaccharides and ellagic acid synergistically enhance muscular endurance via targeting gut microbial urolithin A biosynthesis","authors":"Laiming Zhang,&nbsp;Zengliang Jiang,&nbsp;Donghong Liu,&nbsp;Chengxiao Yu,&nbsp;Yi Wang,&nbsp;Haozhen Zhang,&nbsp;Jiaxiong Wu,&nbsp;Haibo Pan,&nbsp;Xingqian Ye,&nbsp;Shiguo Chen","doi":"10.1016/j.jare.2026.01.017","DOIUrl":"10.1016/j.jare.2026.01.017","url":null,"abstract":"<div><h3>Introduction</h3><div>Sarcopenia, characterized by the progressive loss of muscle mass and function, may be alleviated by ellagic acid (EA) through its microbial metabolite urolithin A (Uro-A). However, the low <em>in vivo</em> conversion efficiency of EA to Uro-A limits its clinical utility.</div></div><div><h3>Objectives</h3><div>This study aimed to develop a gut microbiota-targeted dietary strategy to enhance Uro-A biosynthesis and improve muscle performance.</div></div><div><h3>Methods</h3><div>A combinatorial approach using EA and fructooligosaccharides (FOS) was applied <em>in vivo</em> to modulate microbial metabolism. Gut microbiota composition, urolithin profiles, and muscle performance were assessed. Mechanistic roles of key bacterial species were further explored.</div></div><div><h3>Results</h3><div>EA and FOS synergistically improved muscle endurance and strength by enhancing Uro-A production, compared with either intervention alone. Mechanistically, we identified a previously unrecognized two-step cooperative pathway: <em>Bifidobacterium pseudolongum</em> initiated EA metabolism by converting it to urolithin C (Uro-C), and while <em>Enterococcus faecalis,</em> identified here for the first time, catalyzed the conversion of Uro-C to Uro-A. This newly uncovered cross-feeding partnership between the two species proved essential for maximizing Uro-A biosynthesis and mediating the physiological benefits.</div></div><div><h3>Conclusion</h3><div>This study demonstrates a proof-of-concept strategy to boost gut microbial Uro-A biosynthesis through dietary modulation, providing a novel and cost-effective approach for sarcopenia prevention and management.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 179-192"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial heterogeneity of viral communities across the gastrointestinal tracts of ruminants","authors":"Shizhe Zhang,&nbsp;Qiushuang Li,&nbsp;Yongyi Peng,&nbsp;Jiabin Huo,&nbsp;Tao Ran,&nbsp;Xiumin Zhang,&nbsp;Rong Wang,&nbsp;Jinzhen Jiao,&nbsp;Aoyu Jiang,&nbsp;Guowang Luo,&nbsp;Zhigang Zhang,&nbsp;Qiang Qiu,&nbsp;Zhipeng Li,&nbsp;Shengyong Mao,&nbsp;Zhongtang Yu,&nbsp;Zhiliang Tan,&nbsp;Xiyang Dong,&nbsp;Min Wang","doi":"10.1016/j.jare.2026.01.013","DOIUrl":"10.1016/j.jare.2026.01.013","url":null,"abstract":"<div><h3>Introduction</h3><div>Viruses are abundant biological entities within the gastrointestinal tract (GIT) of ruminants. Current understanding is extensive for bacterial and archaeal communities, but limited for viral communities.</div></div><div><h3>Objectives</h3><div>The study aimed to investigate viral diversity, virus-host interactions and ecological functions of viruses across GIT regions and ruminant species.</div></div><div><h3>Methods</h3><div>We collected 373 short-read and long-read metagenomes from 10 GIT regions of seven ruminant species, combining Illumina, PacBio HiFi, and Nanopore sequencing. Viral contigs were identified using sequence homology, viral hallmark gene and machine learning, and employed to uncover community assembly of spatial heterogeneity by analyzing virus-host linkage, lifestyle, and auxiliary metabolic genes (AMGs).</div></div><div><h3>Results</h3><div>We constructed a Ruminant Gastrointestinal Virome Catalog (RGVC) comprising 43,981 vOTUs, revealing that viral communities were remarkably diverse and mainly driven by the GIT regions rather than by the ruminant species. Virus-host linkage analysis identified 4603 putative prokaryotic hosts across 34 classes for 5954 host-linked viruses, along with robust correlation (<em>R²</em> = 0.91) observed between abundances of prokaryotic hosts and host-linked viruses across GIT regions. The lysogenic lifestyle was a dominant feature, with integrases being the predominant lysogenic-specific genes. We identified 864 high-confidence AMGs in lysogenic viruses that are annotated as key genes for polysaccharide degradation, glycolysis, and the Wood-Ljungdahl pathway, indicating a putative role for the viruses in supporting these host metabolic functions. The metabolic features of host-linked viruses were further verified by genomic context of selected AMGs of GH10, GPI and FHS with target function.</div></div><div><h3>Conclusion</h3><div>These findings suggest that the GIT viral communities exhibit spatial heterogeneity with distinct virus-host interactions, and offer new perspectives on maintenance of complex ecological and nutritional functions in ruminant GIT.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 31-44"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BnaGRP3 mediates salt tolerance via Na+/K+ homeostasis and BnaPIPs interactions in Brassica napus","authors":"Ouqi Li,&nbsp;Min Zou,&nbsp;Xianfei Hou,&nbsp;Jiawen Zhao,&nbsp;Hao Zhang,&nbsp;Chao He,&nbsp;Xinyi Fan,&nbsp;Yifei Jin,&nbsp;Yina Ma,&nbsp;Donghai Jia,&nbsp;Yuanguo Gu,&nbsp;Heping Wan,&nbsp;Jing Wen,&nbsp;Bin Yi,&nbsp;Tingdong Fu,&nbsp;Jinxiong Shen,&nbsp;Lun Zhao","doi":"10.1016/j.jare.2026.01.018","DOIUrl":"10.1016/j.jare.2026.01.018","url":null,"abstract":"<div><h3>Introduction</h3><div>Rapeseed (<em>Brassica napus</em> L.) is a major oilseed crop with considerable potential for improving saline–alkali soils, yet the molecular mechanisms underlying its salt tolerance remain unclear.</div></div><div><h3>Objectives</h3><div>This study investigates the functional roles and regulatory mechanisms of <em>glycine-rich protein 3</em> (<em>BnaGRP3</em>) in rapeseed under salt stress.</div></div><div><h3>Methods</h3><div>We employed molecular genetics, phenotypic and biochemical evaluation of transgenic rapeseed and <em>Arabidopsis</em>, transcriptome sequencing, protein interaction assays including immunoprecipitation–mass spectrometry (IP-MS), yeast two-hybrid (Y2H), luciferase complementation (LCA), and bimolecular fluorescence complementation (BiFC) assays, gene expression analysis by RT-qPCR, and hydrogen peroxide (H₂O₂) permeability assays conducted in yeast.</div></div><div><h3>Results</h3><div><em>BnaGRP3</em> was induced by salt stress and enhanced salt tolerance. Transcriptome analysis revealed that <em>BnaGRP3</em> modulated expression of ion transporters under salt stress, especially <em>NHX1</em> and <em>SKOR</em>. BnaGRP3 physically interacted with four plasma membrane intrinsic proteins (BnaPIPs). Overexpression of these <em>BnaPIPs</em> improved salt tolerance in <em>Arabidopsis</em> and increased H₂O₂ tolerance when expressed in yeast. In addition, these BnaPIPs formed both homomeric and heteromeric complexes, suggesting they may facilitate H₂O₂ permeability.</div></div><div><h3>Conclusions</h3><div>BnaGRP3 enhances salt tolerance by maintaining Na⁺/K⁺ homeostasis and, through its interactions with BnaPIPs, may participate in the regulation of H₂O₂ balance·H₂O₂ potentially serves as a bridge linking BnaGRP3-mediated ion homeostasis and redox regulation. The previously uncharacterized BnaGRP3–BnaPIP module broadens the mechanistic framework of GRP-mediated salt stress responses, thereby expanding our understanding of salt tolerance mechanisms in <em>Brassica napus</em>.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 61-75"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bio-inspired supramolecular hydrogel inhibits ferroptosis to accelerate diabetic wound healing","authors":"Haiting Zou,&nbsp;Jingyi Chen,&nbsp;Yumeng Huang,&nbsp;Jiaye Li,&nbsp;Xuemei Yuan,&nbsp;Tianzhe Chen,&nbsp;Youjun Ding,&nbsp;Ping Yang,&nbsp;Dongfeng Zheng,&nbsp;Guopu Chen,&nbsp;Qian Tan","doi":"10.1016/j.jare.2026.01.024","DOIUrl":"10.1016/j.jare.2026.01.024","url":null,"abstract":"<div><h3>Introduction</h3><div>Ferroptosis significantly compromises diabetic wound healing and represents a promising therapeutic target for clinical intervention. Baicalein (Bai), a natural flavonoid, has been considered to own ferroptosis-regulating properties, while the underlying mechanisms remain understood.</div></div><div><h3>Objectives</h3><div>The study aims to investigate potential mechanisms by which Bai inhibits ferroptosis in endothelial cells and validate the therapeutic efficacy of Bai-loaded hydrogel on diabetic wounds.</div></div><div><h3>Methods</h3><div>High-glucose-cultured human umbilical vein endothelial cells (HUVECs) were chosen to study Bai’s molecular mechanisms inhibiting ferroptosis. Subsequently, a Bai@GA/Gel/Zn²⁺ supramolecular nanofibrous hydrogel was developed for active Bai delivery. Its wound-healing efficacy and underlying mechanisms were further evaluated in a diabetic rat model.</div></div><div><h3>Results</h3><div><em>In vitro</em> experiments, HUVECs were observed to exhibit characteristic ferroptosis, which were induced by high-glucose (HG) microenvironment, leading to compromised cellular functions. Through the inhibition of ferroptosis in HUVECs, Bai effectively promoted cell growth, migration, and angiogenesis. Herein, we further reveal that Bai inhibits HG-induced ferroptosis by modulating the Keap1/NRF2/HIF-1α signaling axis. To optimize therapeutic delivery, Bai was encapsulated into supramolecular nanofibers self-assembled from glycyrrhizic acid (GA), followed by cross-linking with gelatin (Gel) and zinc ions (Zn²⁺) to form a hydrogel (Bai@GA/Gel/Zn²⁺), thereby enabling sustained release of Bai at the wound-healing interface. Bai@GA/Gel/Zn²⁺ nanofiber-incorporated hydrogel demonstrated favorable mechanical and biological properties, markedly reducing ferroptosis levels and accelerating diabetic wound healing.</div></div><div><h3>Conclusion</h3><div>In summary, our findings reveal the ferroptosis-inhibiting mechanism of Bai and develop a Bai@GA/Gel/Zn²⁺ supramolecular nanofibrous hydrogel that synergistically enhances diabetic wound healing with proven therapeutic efficacy.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 841-853"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactylation at the metabolic-epigenetic interface in cardiovascular diseases: context-dependent mechanisms and translational roadmap","authors":"Guilin Cheng,&nbsp;Yan Liu,&nbsp;Yangkun Xing,&nbsp;Zhewei Shi,&nbsp;Mohamed Ali Farag,&nbsp;Songheng Jin,&nbsp;Bo Xia","doi":"10.1016/j.jare.2026.01.007","DOIUrl":"10.1016/j.jare.2026.01.007","url":null,"abstract":"<div><div><strong>Background:</strong> Lysine lactylation has redefined lactate’s biological role from a metabolic byproduct to a signaling molecule. This post-translational modification directly couples cellular energetics with gene regulation, creating a metabolic-epigenetic axis particularly relevant to cardiovascular pathophysiology. Ischemic and inflammatory stress drive glycolytic reprogramming and lactate accumulation in these diseases. Lactylation modifies both histone and non-histone proteins, enabling metabolic states to reshape chromatin accessibility and protein function. However, therapeutic translation faces critical barriers. These include incomplete characterization of the cardiovascular lactylome, absence of selective pharmacological modulators, and insufficient understanding of how lactylation effects vary across cell types, disease stages, and metabolic contexts.</div><div><strong>Aim of Review</strong>: We systematically dissect lactylation biology across 5 cardiovascular pathologies to define regulatory mechanisms and therapeutic vulnerabilities. We examine glycolysis-lactylation circuits driving pulmonary arterial smooth muscle hyperproliferation in hypertension; dual roles in atherosclerotic plaque stability versus calcification; M2 macrophage-mediated repair versus fibrotic remodeling in myocardial infarction; the metabolic paradox of lactate accumulation with reduced α-myosin heavy chain lactylation impairing contractility in heart failure; and neonatal glycolytic metabolism enabling histone lactylation-driven cardiomyocyte proliferation with metabolic barriers in diabetic contexts.</div><div><strong>Key Scientific Concepts of Review</strong>: Lactylation functions through dual substrates: histone modifications orchestrate inflammatory resolution and cell cycle activation, while non-histone modifications (α-myosin heavy chain, Snail1) directly govern contractility and pathological remodeling. Context-dependent dichotomies emerge across diseases, with protective angiogenesis versus maladaptive fibrosis in infarction and plaque stabilization versus calcification in atherosclerosis. Critically, metabolic paradoxes challenge lactate-lactylation correlations: heart failure shows lactate accumulation yet reduced modification, while diabetic advanced glycation end-products competitively inhibit lactylation. Therapeutic strategies require integrating metabolic reprogramming, site-selective targeting, and temporal control. This review systematically dissects these mechanistic complexities to establish a translational framework that guides precision cardiovascular medicine through metabolic-epigenetic intervention strategies.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 193-212"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Guaianolide dimer KGA-1002 targets GRP94 and triggers unfolded protein response-associated degradation of SKP2/AKT axis as a novel antihepatoma agent","authors":"Qi-Hao Li,&nbsp;Tian-Ze Li,&nbsp;Yong-Cui Wang,&nbsp;Xiao-Yan Huang,&nbsp;Wen-Jing Ma,&nbsp;Feng-Jiao Li,&nbsp;Feng-Dan Huang,&nbsp;Min-Min Hu,&nbsp;Ji-Jun Chen","doi":"10.1016/j.jare.2026.01.010","DOIUrl":"10.1016/j.jare.2026.01.010","url":null,"abstract":"<div><h3>Introduction</h3><div>Hepatocellular carcinoma (HCC) remains a highly lethal malignant tumor with limited treatment options. The guaianolide dimer KGA-1002 exhibited significant inhibitory effects on HCC cells, but the specific target and mechanism remain unclear.</div></div><div><h3>Objectives</h3><div>To further evaluate the antiHCC efficacy of KGA-1002 and clarify its molecular target and mechanism.</div></div><div><h3>Methods</h3><div>BrdU, flow cytometry, Transwell, and colony formation assays were utilized to evaluate the <em>in vitro</em> antiHCC efficacy of KGA-1002. Drug affinity responsive target stability (DARTS) and bioinformatics analyses were applied to identify its target. The binding site was confirmed through Mass spectra analysis and amino acid mutation. Knockdown cell lines were used to validate the GRP94-dependent effects of KGA-1002. Pulldown assays were performed to detect protein–protein interactions. Xenograft tumor models were employed to examine the <em>in vivo</em> efficacy and mechanism.</div></div><div><h3>Results</h3><div>KGA-1002 inhibited the proliferation and metastasis of HCC cells, induced apoptosis and cell-cycle arrest at the G0/G1 phase. GRP94 was identified as its direct target, and Ser¹⁰⁶ was confirmed as the covalent binding site. KGA-1002 targeting GRP94 triggered the unfolded protein response (UPR)-associated degradation and disrupted the GRP94-AKT interaction, resulting in AKT degradation. The degradation of AKT induced ferroptosis and reduced the stability of SKP2. The impairment of AKT and SKP2 promoted the nuclear accumulation of P21, which further induced apoptosis in HCC cells. <em>In vivo</em>, KGA-1002 (60 mg/kg) inhibited tumor growth by 61.6 %, and the effect was GRP94-dependent.</div></div><div><h3>Conclusion</h3><div>KGA-1002 was identified as a highly promising lead compound for antiHCC. Its mechanism involved triggering UPR-associated degradation and disrupting the GRP94-AKT interaction. KGA-1002 simultaneously induced apoptosis and ferroptosis in HCC cells through the GRP94/AKT/SKP2/P21 signaling axis.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 1077-1093"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia inhibits intervertebral disc degeneration by maintaining autophagy circadian rhythm via the HIF1α-PER2-mTOR pathway","authors":"Guang-Cheng Yuan,&nbsp;Qi-Chen Zhang,&nbsp;Yu-Xiang Ge,&nbsp;Heng-Jie Zeng,&nbsp;Tai-Wei Zhang,&nbsp;Wang Ding,&nbsp;Zhi-Rui Dong,&nbsp;Yu-Kai Huang,&nbsp;Jian Dong,&nbsp;Nong Chen,&nbsp;Li-Bo Jiang","doi":"10.1016/j.jare.2025.12.036","DOIUrl":"10.1016/j.jare.2025.12.036","url":null,"abstract":"<div><h3>Introduction</h3><div>Disruption of the circadian rhythm (CR) and autophagy in intervertebral discs contributes to intervertebral disc degeneration (IDD) progression. However, the circadian regulation of autophagy requires further investigation.</div></div><div><h3>Objectives</h3><div>We observed the expression of circadian proteins and autophagic markers of nucleus pulposus (NP) cells followed a diurnal rhythmic pattern in vivo and in vitro.</div></div><div><h3>Methods</h3><div>NP tissues were collected from light/dark cycle–shifted rats and IDD patients of varying severity. CR and ECM-related proteins were analyzed by immunohistochemistry and western blotting. Primary rat NP cells were treated with hypoxia or CoCl₂, followed by western blotting for CR proteins, HIF-1α, and autophagy markers. siRNA knockdown of PER2 or HIF-1α was performed to assess their roles in regulating autophagy, ECM, and CR-associated proteins.</div></div><div><h3>Results</h3><div>The silencing of clock gene PER2 disrupted the rhythmic expression of autophagic markers, by contrast PER2 overexpression inhibited mTOR pathway and enhanced autophagic levels. Co-IP analysis demonstrated the PER2-mTOR interaction, linking CR and autophagy rhythm. The inflammatory stimulator dampened the CR and autophagy rhythm, however intermittent hypoxia and cobalt chloride (CoCl₂) re-synchronized the rhythm. Mechanistically, HIF-1α-mediated regulation of PER2 by hypoxia was involved in the re-synchronization, which was further demonstrated by the loss of CR and autophagy rhythm after silencing of PER2 or HIF-1α under hypoxia. Furthermore, the rhythm of oxygen level and HIF-1α was proved in living healthy NP tissue, confirming the hypoxia as a Zeitgeber. CR disruption and autophagy dysfunction led to catabolism of extracellular matrix (ECM), but the hypoxia, CoCl₂ and autophagic stimulator could promote the rebalance of ECM metabolism.</div></div><div><h3>Conclusion</h3><div>Our study demonstrates that hypoxia maintains the intrinsic CR and autophagy rhythm through the HIF-1α/PER2/mTOR pathway to prevent IDD.</div></div>","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"88 ","pages":"Pages 759-774"},"PeriodicalIF":17.1,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145866980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}