Journal of advanced research最新文献

{"title":"Integrated single-cell and spatial transcriptomic analyses identify a unique subset of pro-fibrotic macrophages in kidney fibrosis.","authors":"Liuyan Xiao, Yinyi Long, Xue Hong, Xi Liu, Yu Hu, Xin Xu, Youhua Liu","doi":"10.1016/j.jare.2026.08.041","DOIUrl":"10.1016/j.jare.2026.08.041","url":null,"abstract":"<p><strong>Introduction: </strong>Acute kidney injury (AKI) is a severe clinical syndrome associated with high morbidity and mortality, and it possesses high risk of progression to chronic kidney disease (CKD). Renal infiltration of inflammatory cells, particularly macrophages, plays a key role in driving the progression from AKI to CKD.</p><p><strong>Methods: </strong>We performed single-cell RNA sequencing and spatial transcriptomics analyses on mouse kidney tissues after unilateral ischemia-reperfusion injury (UIRI) at multiple time points (sham, 12 h, 1 day, 4 days, and 10 days post-UIRI). Immunofluorescence, flow cytometry, Western blotting, co-immunoprecipitation, surface plasmon resonance and immunohistochemical staining were applied to investigate protein expression and function.</p><p><strong>Results: </strong>Six distinct mononuclear phagocyte (MNP) subpopulations were identified and each of them exhibited a unique set of gene expression patterns. In particular, we uncovered an injury-induced, spatially distinct macrophage subset with specific profibrotic properties, named as pro-fibrotic macrophages (PFMs). During the progression of AKI to CKD, PFMs secreted thrombospondin-1 (THBS1), which interacted with and activated LDL receptor-related protein 1 (LRP1) on adjacent interstitial fibroblasts, thereby promoting fibroblast activation and proliferation. In cultured kidney fibroblasts, THBS1 induced fibroblast activation and matrix production, and blockade or knockdown of LRP1 abolished this effect. Furthermore, THBS1 activated a cascade of LRP1 downstream signaling mediators including focal adhesion kinase, protein kinase B, and extracellular signal-regulated kinase 1 and 2. THBS1 also promoted TGF-β1 activation in a LRP1-dependent manner in fibroblasts. In humans, urinary THBS1 levels predicted the rate of CKD progression.</p><p><strong>Conclusion: </strong>These studies identify a unique subset of pro-fibrotic macrophages that drive fibroblast activation through THBS1/LRP1 signaling in a spatially confined setting. Our findings suggest that PFMs-derived THBS1 contributes to the progression from AKI to CKD.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PhaseOM: an integrated multi-task framework for phase separation analysis and key residue detection.","authors":"Liping Xu, Shengming Zhou, Zixu Ran, Xianmian Qin, Tian Liu, Quan Zou, Fuyi Li, Cangzhi Jia","doi":"10.1016/j.jare.2026.08.052","DOIUrl":"10.1016/j.jare.2026.08.052","url":null,"abstract":"<p><strong>Introduction: </strong>Liquid-liquid phase separation (LLPS) drives cellular organization through scaffold proteins that initiate condensate formation and client proteins that partition into them. Current computational tools lack precision in differentiating these functional classes and identifying key intrinsically disordered regions (IDRs), limiting mechanistic understanding of LLPS in health and disease.</p><p><strong>Objectives: </strong>This study develops PhaseOM, a unified computational framework to: (1) differentiate scaffold versus client proteins; (2) identify LLPS-associated IDRs; and (3) pinpoint critical functional residues, enabling systematic analysis of LLPS determinants.</p><p><strong>Methods: </strong>We constructed a multi-task predictive framework. Standard datasets were curated from drLLPS and PDB. PhaseOM integrates four specialized models: (1) a Graph Attention Network fusing ProtT5 sequence embeddings and ESMFold-predicted structural features for scaffold identification; (2) an ensemble classifier leveraging 22 optimized physicochemical and structural attributes for client discrimination; (3) a model based on 17 disorder-related features for IDR detection; and (4) a deep multi-layer perceptron with multi-head self-attention for key residue prediction. The performance of these models was thoroughly assessed using independent test datasets to ensure robustness and reliability.</p><p><strong>Results: </strong>PhaseOM outperformed Seq2Phase on independent tests, achieving scaffold AUC of 0.9954 and client AUC of 0.9474 (MCC 0.7514). It improved client AUC by 0.21 and scaffold AUC by >0.07 over baseline. Key findings reveal that scaffolds are enriched in tyrosine/arginine, facilitating multivalency, while clients exhibit expanded conformations with cysteine/histidine enrichment. Empirical validation on α-synuclein isoforms confirmed high-fidelity predictions, with residue-level IDR accuracy ranging from 76% to 91%. PhaseOM provides the first unified platform for systematic proteome-wide phase separation analysis.</p><p><strong>Conclusion: </strong>PhaseOM provides the first unified platform for comprehensive LLPS analysis, revealing distinct mechanistic principles and enabling rational design of biomolecules with tunable phase behavior for therapeutic applications.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803830","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical force activates KCNN4 to regulate the NLRP3 inflammasome in periodontal ligament cells during orthodontic tooth movement.","authors":"Fu Zheng, Feifei Wang, Peng Chen, Peng Wang, Chen Yang, Chonghao Ji, Zuping Wu, Xinyi Fang, Xinlei Yu, Lehan Xu, Jing Zhou, Rui Zhang, Gaofeng Li, Peng Deng, Qianming Chen, Xiaoyan Chen","doi":"10.1016/j.jare.2026.08.049","DOIUrl":"10.1016/j.jare.2026.08.049","url":null,"abstract":"<p><strong>Introduction: </strong>Orthodontic tooth movement (OTM) relies on mechanical force that triggers inflammatory responses in periodontal tissue, orchestrating alveolar bone remodeling. Potassium (K⁺) efflux plays a key role in inflammation and tissue remodeling. The calcium-activated potassium channel KCNN4 regulates immune responses, but its role in inflammatory signaling in periodontal ligament cells (PDLCs) under mechanical stress remains unclear.</p><p><strong>Objectives: </strong>This study aimed to investigate how mechanical force activates KCNN4 and regulates downstream inflammatory signaling in PDLCs.</p><p><strong>Methods: </strong>Human PDLCs (hPDLCs) were subjected to compressive force in vitro. KCNN4, FOXO1, and USP46 were interfered with using pharmacological inhibition (senicapoc) or siRNA-mediated knockdown. Potassium and calcium fluxes, NLRP3 inflammasome activation, and downstream cytokine expression were assessed via fluorescence imaging, western blotting, qPCR, and immunoprecipitation. Chromatin immunoprecipitation and RNA-seq analyses were performed to identify transcriptional regulators of USP46. Conditioned medium from hPDLCs was applied to THP-1-derived macrophages to evaluate macrophage inflammatory polarization. In vivo, a rat OTM model was used to examine alveolar bone remodeling and local inflammation under KCNN4 inhibition. TRAP staining, immunohistochemistry, and immunofluorescence to evaluate osteoclast activity and NLRP3-mediated inflammatory signaling in the periodontal ligament.</p><p><strong>Results: </strong>Mechanical force induced KCNN4-mediated K⁺ efflux in hPDLCs, promoting FOXO1 dephosphorylation and nuclear translocation. Activated FOXO1 transcriptionally upregulated the deubiquitinase USP46, which in turn deubiquitinated NLRP3, leading to inflammasome activation. Inhibition of KCNN4, FOXO1, or USP46 attenuated NLRP3 activation and downstream IL-1β maturation. Conditioned medium experiments demonstrated that this signaling cascade promoted macrophage inflammatory activation, while senicapoc reversed these effects. In vivo, KCNN4 inhibition suppressed local NLRP3-mediated inflammation, reduced osteoclast differentiation on the pressure side, and attenuated OTM.</p><p><strong>Conclusions: </strong>Our findings reveal a mechanotransduction axis in PDLCs whereby mechanical force activates KCNN4, driving FOXO1-dependent USP46 transcription and NLRP3 inflammasome activation. This signaling cascade translates transient mechanical stimuli into an inflammatory cascade, triggering macrophage-mediated alveolar bone remodeling during OTM. Importantly, KCNN4 is required for proper inflammatory responses and OTM, highlighting its potential role in orthodontic therapy.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of modifiable factors associated with Pan-Cancer Risk: An Exposome-Wide analysis.","authors":"Wen Liu, Shuai Xiang, Yiwei Liu, Guiming Zhang, Lu Yin, Dong Chen, Wenkuan Wang, Feiya Yang, Wenqiang Wei, Nianzeng Xing","doi":"10.1016/j.jare.2026.08.048","DOIUrl":"10.1016/j.jare.2026.08.048","url":null,"abstract":"<p><strong>Introduction: </strong>Hypothesis-driven studies have identified many modifiable cancer risk factors, but research focusing on single exposures overlooks their complex interactions.</p><p><strong>Objectives: </strong>This study applied an exposome-wide approach across multiple cancer types to systematically identify modifiable exposures and evaluate their combined effects with genetic susceptibility.</p><p><strong>Methods: </strong>We analyzed data from over 460,000 UK Biobank participants with 15 years of follow-up, assessing 93 modifiable exposures in relation to 23 site-specific cancers using Cox models. Exposomic risk scores (ERS) were constructed to quantify the combined effects of identified factors. Population attributable fractions (PAFs) were calculated to estimate the potential population-level burden associated with these factors. Finally, polygenic risk scores (PRS) were incorporated to evaluate the relative contributions of genetic susceptibility and modifiable exposures to cancer risk.</p><p><strong>Results: </strong>We identified 209 significant exposure-cancer risk estimates, with both their number and magnitude varying markedly across cancer types. Lung cancer exhibited the largest number of associations, whereas ovarian, testicular, and brain cancers showed no significant associations. Several exposures were associated with multiple cancers, such as basal metabolic rate, smoking, diabetes, household income, alcohol consumption, and body fat percentage, suggesting pleiotropic effects. ERSs summarized the combined influence of these modifiable exposures, and PAFs estimated their potential contribution to the population-level cancer burden across cancer types (4.5%-75.6%). PRS integration showed larger relative genetic contributions for prostate cancer (48.6%), melanoma (48.9%), and Hodgkin lymphoma (61%), while modifiable exposures were more influential in endometrial cancer (74.2%), lung cancer (71.1%), and liver cancer (57.8%).</p><p><strong>Conclusion: </strong>This study provides a pan-cancer, exposome-wide perspective on modifiable and genetic contributions to cancer risk, highlighting the potential value of targeting controllable exposures to reduce population-level cancer burden.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting a candidate stromal immune checkpoint: a cellular senescence signature identifies COMP⁺ cancer-associated fibroblasts associated with CD8⁺ T-cell exclusion via a predicted COMP-CD47 axis in colorectal cancer.","authors":"Yingying Chen, Ying Zhang, Chi Lv","doi":"10.1016/j.jare.2026.08.047","DOIUrl":"10.1016/j.jare.2026.08.047","url":null,"abstract":"<p><strong>Introduction: </strong>Resistance to immunotherapy in colorectal cancer (CRC) is closely linked to an immunosuppressive tumour microenvironment (TME), in which cancer-associated fibroblasts (CAFs) are key regulators. Cellular senescence and the senescence-associated secretory phenotype (SASP) are increasingly recognised as drivers of CAF activity, yet their systematic prognostic and immunomodulatory value in CRC remains poorly defined.</p><p><strong>Methods: </strong>Using transcriptomic and clinical data from the TCGA-COADREAD cohort, we screened differentially expressed cellular senescence-related genes (DE-CSRGs) and constructed a prognostic signature, externally validated in independent GEO cohorts (GSE39582). Multi-omics analyses-functional enrichment, immune-infiltration estimation, single-cell and spatial transcriptomics, and ligand-receptor inference-were integrated to characterise the associated biology, and findings were validated at the protein level by multiplex immunofluorescence and immunohistochemistry in an independent pMMR CRC cohort.</p><p><strong>Results: </strong>We established and validated a five-gene senescence signature (COMP, MMP3, MMP1, EPHX4, PLCD4). After adjustment for tumour purity, stromal content and CMS subtype, the signature remained independently prognostic and was enriched in the mesenchymal (CMS4) subtype. The high-risk group showed stromal remodelling, epithelial-mesenchymal transition and an immunosuppressive phenotype with CD8⁺ T-cell exclusion. Single-cell analysis localised COMP to a myofibroblastic CAF subset exhibiting a non-inflammatory senescence phenotype (up-regulated CDKN2A/CDKN1A/SERPINE1 with suppressed IL6/NF-κB SASP). Spatial transcriptomics and tissue staining confirmed spatial co-localisation of COMP⁺ CAFs with reduced CD8⁺ T-cell density. Ligand-receptor inference nominated the thrombospondin-family COMP-CD47 pair as a predicted interaction associated with, but not proven to cause, this immune-excluded phenotype.</p><p><strong>Conclusion: </strong>We describe an immunosuppressive CRC subtype defined by a senescence signature and associated with COMP⁺ CAFs. We propose the predicted COMP-CD47 axis as a candidate stromal immune-checkpoint that warrants functional validation, rather than an established therapeutic target.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148803753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered marbled meat through EPA-mediated co-differentiation of porcine muscle and fat progenitors without conventional hormonal induction.","authors":"Xin Gu, Shiyuan Hua, Teresa G Valencak, Lay Poh Tan, Min Zhou, Tizhong Shan","doi":"10.1016/j.jare.2026.08.043","DOIUrl":"10.1016/j.jare.2026.08.043","url":null,"abstract":"<p><strong>Introduction: </strong>Intramuscular fat, known as \"snowflake\" pattern in pork, critically determines meat tenderness, juiciness, flavor, and overall consumer preference. Cultured meat has emerged as a promising solution to address future protein demands sustainably. However, producing cultured meat with authentic marbling remains challenging, as myocytes and adipocytes require distinct microenvironments for differentiation.</p><p><strong>Objective: </strong>This study aimed to develop a co-differentiation strategy independent of conventional hormonal adipogenic cocktails (IBMX and dexamethasone) to simultaneously induce myogenesis and adipogenesis in a single culture system, thereby enabling the production of structured cultured meat with microscale muscle-fat patterning.</p><p><strong>Methods: </strong>An edible κ-carrageenan-konjac glucomannan (CK) hydrogel was developed as a versatile platform for cultured meat. A 3D co-culture system was established by encapsulating porcine muscle satellite cells (pMuSCs) and fibro-adipogenic progenitors (pFAPs) within the CK scaffold, followed by differentiation induction using an eicosapentaenoic acid (EPA, C20:5n-3)-based strategy. The physicochemical properties of the resulting cultured meat induced with EPA (CM-EPA) were rigorously characterized using texture profile analysis and nutritional composition analysis, with comparisons made against horse serum-induced controls (CM-HS) and commercial streaky pork.</p><p><strong>Results: </strong>The CK hydrogel exhibited tunable, biomimetic mechanical properties and a porous microstructure that supported the proliferation and differentiation of both cell lineages. Notably, the EPA-based induction strategy significantly enhanced lipid accumulation while simultaneously supporting myotube formation from pMuSCs, effectively mitigating the myogenesis inhibition associated with conventional hormonal adipogenic cocktails. The co-cultured meat exhibited significantly improved textural properties, such as hardness and chewiness, which closely resembled those of real streaky pork. Its nutritional profile also showed elevated protein and fat content relative to the CM-HS control.</p><p><strong>Conclusion: </strong>This work establishes a versatile scaffold-based platform for producing structured cultured meat with integrated muscle and fat components, offering a promising strategy to replicate the textural and nutritional qualities of traditional meat.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148766019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nutraceutical and functional food: efficacy against metabolic disorders and underlying mechanistic insights.","authors":"Qihui Yang, Yuxin Pei, Luyao Zhao, Yuzhen Wang, Huilin Liu, Baoguo Sun","doi":"10.1016/j.jare.2026.08.018","DOIUrl":"10.1016/j.jare.2026.08.018","url":null,"abstract":"<p><strong>Background: </strong>The growing global emphasis on health consciousness has significantly increased demand for traditional and complementary medicine products, including functional foods, nutraceuicals, and medicine and food homologous substances (MFHs). The rising prevalence of chronic diseases and the shift toward preventive healthcare have accelerated this market expansion. Although MFHs have been applied for hundreds of years in traditional healthcare systems, contemporary research faces a critical knowledge gap in the systematic organization of scientific evidence.</p><p><strong>Aim of the review: </strong>This review systematically summarizes the major bioactive compounds and extraction methods of MFHs with therapeutic potential against MetS. It further discusses the molecular mechanisms underlying their effects on hypertension, hyperglycemia, dyslipidemia, and hyperuricemia, while highlighting current challenges related to safety and clinical translation.</p><p><strong>Key scientific concepts of the review: </strong>MFHs contain diverse bioactive constituents, including polysaccharides, saponins, flavonoids, polyphenols, alkaloids, and terpenoids, which exert beneficial effects on multiple components of MetS through the regulation of oxidative stress, inflammation, energy metabolism, and other signaling pathways. Conventional and emerging extraction technologies have improved the recovery and utilization of these compounds, supporting their applications in functional foods, nutraceuticals, and therapeutic products. Despite promising preclinical evidence, further studies are required to standardize extraction processes, validate efficacy and safety, and strengthen clinical evidence to facilitate the development and application of MFHs in MetS prevention and management.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing the battle against panama disease: a critical appraisal of global biocontrol research and applications.","authors":"Han Liangliang, Ali Qurban, Chen Yufeng, Wang Wei, Raza Waseem, Xie Jianghui","doi":"10.1016/j.jare.2026.08.039","DOIUrl":"10.1016/j.jare.2026.08.039","url":null,"abstract":"<p><strong>Background: </strong>Banana, the fourth most important food crop globally, is severely threatened by Panama disease caused by Fusarium oxysporum f. sp. cubense (Foc). The continued spread of Foc tropical race 4 (TR4), with recent first reports in Peru and Venezuela, demands renewed attention and a critical reevaluation of eco-friendly management strategies. Biocontrol has emerged as a promising approach, but its efficacy varies widely across studies and geographic regions, and a comprehensive synthesis of research trends and outcomes is lacking.</p><p><strong>Aim of review: </strong>This review critically synthesizes the past decade of biocontrol research on Panama disease, examining geographic and taxonomic trends, biocontrol efficiency, and methodological factors including strain isolation sources, pathogen races, plant growth media, soil amendments, and application methods. We aim to identify persistent patterns alongside novel developments, critically evaluate outcomes, discuss reasons for inconsistencies, and provide future recommendations to achieve the greatest success in combating Panama disease.</p><p><strong>Key scientific concepts of review: </strong>A systematic literature search yielded 123 studies, which were analyzed using random-effects meta-analysis with logit transformation. Research trends vary significantly by country and microbial group, revealing distinct regional and taxonomic methodological approaches and success rates. Overall, Streptomyces and Trichoderma emerged as the most effective genera, particularly against Foc TR4, with optimal conditions identified as: sterilized medium or field conditions, without amendments, multiple-strain SynComs, non-banana bulk soil isolates, multiple applications, and soil drenching or dual-application methods. However, current research remains geographically centralized and taxonomically narrow. Efficacy is highly context-dependent, shaped by geography, microbial genus, and methodological factors. The review identifies critical knowledge gaps, including limited field validation, incomplete reporting of experimental parameters, and publication bias, and calls for standardized reporting, expanded exploration of understudied regions and microbial sources, and integrated, multi-disciplinary approaches to translate research into practical solutions for sustainable banana production.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148763324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dual-target modulator of STK11 and PP2Acα from the flowers of Chrysanthemum indicum mitigates drug-induced liver injury.","authors":"Fei Zhou, Yu Liu, Haoyu Zhao, Wencai Ye, Qingwen Zhang, Ligen Lin","doi":"10.1016/j.jare.2026.08.044","DOIUrl":"10.1016/j.jare.2026.08.044","url":null,"abstract":"<p><strong>Introduction: </strong>Hormesis, characterized by low-dose stimulation and high-dose inhibition, is a biphasic regulatory phenomenon, and its underlying mechanisms remain elusive. Drug-induced liver injury (DILI) can progress to liver fibrosis, liver failure, and ultimately death, and natural products hold considerable promise for the treatment of DILI.</p><p><strong>Objectives: </strong>To identify the active constituents and underlying biphasic regulatory mechanism of Chrysanthemum indicum against DILI.</p><p><strong>Methods: </strong>Structural elucidation of the new compounds was achieved through integrated interpretation of HRESIMS, 1D and 2D NMR, and ECD. Signaling pathway was determined by mitochondrial transplantation in vitro and in vivo and RNA sequencing. Target proteins were validated by the drug affinity responsive target stability-mass spectrometry analyses, isothermal titration calorimetry, cellular thermal shift assay, shRNA, and liver-specific knockdown mice. Protein sites were validated by truncation experiments, molecular dynamics simulations, and point mutations.</p><p><strong>Results: </strong>A total of 21 guaianolide sesquiterpenoids, including 13 new ones, were isolated and identified from the flowers of C. indicum. Interestingly, the new compound chrysanthemolide I (CI) alleviated acetaminophen-induced liver injury in vitro and in vivo. Mitochondria isolated from CI-treated hepatocytes attenuated DILI. CI attenuated AMP-activated protein kinase (AMPK)-mediated mitochondrial oxidative stress while enhancing AMPK-dependent mitochondrial biogenesis and mitophagy. At low doses, CI binds directly to ALA-205 and ARG-301 of serine/threonine kinase 11 (STK11) with high affinity to activate AMPK; at medium doses, binding of CI to STK11 reaches saturation, leading to peak AMPK activity; at high doses, CI additionally binds to SER-261 of serine/threonine-protein phosphatase 2A catalytic subunit α isoform (PP2Acα) with low affinity to inhibit AMPK activation. Furthermore, liver-specific knockdown of both STK11 and PP2Acα largely diminished the protective effect of CI against DILI.</p><p><strong>Conclusion: </strong>Novel guaianolide sesquiterpenoid CI was identified as an affinity-dependent dual-target regulator of STK11 and PP2Acα to alleviate DILI.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polydatin in combination with hawthorn flavonoids alleviates atherosclerosis by inhibiting mitochondrial division through the YTHDF2-DRP1 axis.","authors":"Yujuan Li, Xiaonan Zhang, Shengjie Yang, Xin Bai, Xiaoya Li, Lanqing Hu, Changxin Sun, Yu Cao, Tong Li, Yongfang Yuan, Lingling Li, Longtao Liu, Min Wu","doi":"10.1016/j.jare.2026.08.037","DOIUrl":"10.1016/j.jare.2026.08.037","url":null,"abstract":"<p><strong>Introduction: </strong>The combination of polydatin and hawthorn flavonoids (PH), a traditional Chinese medicine formulation for activating blood circulation and detoxification, has shown the potential to counteract atherosclerosis, but the mechanisms underlying its effects remain unclear.</p><p><strong>Purpose: </strong>To investigate the protective effects of pH on atherosclerosis and identify the key targets underlying mitochondrial homeostasis.</p><p><strong>Methods: </strong>An ApoE^-/- mouse model fed a high-fat diet (HFD) was established to evaluate the effect of pH on aortic plaques, and an oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cell (HUVEC) injury model was established. Dynamin-related protein 1 (DRP1) knockdown, YTHDF2 knockdown, and overexpression models were used to identify the key targets.</p><p><strong>Results: </strong>PH exerted potent dose-dependent anti-atherosclerotic effects in high-fat diet-challenged ApoE^-/^-mice, reducing atherosclerotic lesion burden by 44.8%, 49.29%, and 72.99% at low, medium, and high doses, respectively. In vivo, PH ameliorated systemic dyslipidemia by lowering circulating total cholesterol, triglycerides, low-density lipoprotein cholesterol, and very-low-density lipoprotein levels, while robustly suppressing proinflammatory cytokine expression. PH also rescued aortic mitochondrial damage, mitigated mitochondrial fragmentation, and restored mitochondrial structural integrity, as evidenced by increased mitochondrial length, improved aspect ratio, and elevated mtDNA abundance. In ox-LDL-injured human umbilical vein endothelial cells (HUVECs), PH rescued endothelial mitochondrial dysfunction and restored normal mitochondrial architecture by reversing the ox-LDL-induced declines in mitochondrial matrix diameter and aspect ratio. Mechanistically, PH inhibited DRP1 expression and Ser616 phosphorylation, blocked mitochondrial translocation of phosphorylated DRP1, and thereby preserved mitochondrial membrane potential and mtDNA content. DRP1 knockdown abrogated PH's endothelial protective functions, verifying DRP1 as a core downstream effector. PH significantly upregulated YTHDF2 expression in ox-LDL-stimulated HUVECs. Functional assays confirmed a negative YTHDF2-DRP1 regulatory axis: YTHDF2 depletion increased DRP1 and phosphorylated DRP1 levels by 31.92% and 30.79%, whereas YTHDF2 overexpression reduced their levels by 43.88% and 38.31%. Notably, YTHDF2 loss abolished PH-mediated DRP1 suppression, indicating PH alleviates DRP1-dependent mitochondrial dysfunction via a YTHDF2-dependent mechanism.</p><p><strong>Conclusion: </strong>PH exerts a protective effect on HUVECs and prevents AS by regulating the YTHDF2/DRP1 axis to restore mitochondrial homeostasis, thereby providing a novel therapeutic approach for AS.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148766480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}