Journal of Advanced Research最新文献

{"title":"Circular RNA-mediated regulation of key signaling pathways in cardiovascular diseases: a review","authors":"Qianhui You, Weiwei Zhang, Chinying Koo, Chengyao Jia, Michail Spanos, Baonian Liu, Junjie Xiao, Haidong Guo","doi":"10.1016/j.jare.2025.09.048","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.048","url":null,"abstract":"Cardiovascular diseases (CVDs) are globally prevalent pathologies driven by dysregulated signaling networks. Circular RNAs (circRNAs), a class of covalently closed non-coding RNAs produced by back-splicing<!-- --> <!-- -->mechanism, in which a downstream 5′ splice site joins an upstream 3′ splice site, have emerged as critical regulators of CVD pathogenesis. This review examines their lifecycle, including biogenesis, nuclear export mechanisms, subcellular localization, and degradation, along with their functional roles in microRNA sequestration, protein interactions, transcriptional regulation, and polypeptide translation. Recent advances in circRNA engineering are also discussed, including <em>in vitro</em> synthesis strategies, delivery platforms, vaccine development, gene editing, and aptamers (synthetic high-affinity nucleic acid ligands).<!-- --> <!-- -->Furthermore, we explore the latest findings that focus on how circRNAs modulate these core CVD-related pathways. The unique expression patterns and engineering potential of circRNAs render them valuable candidates for biomarker and therapy development. This review connects the fundamental biology of circRNAs to recent technological advances, offering a roadmap for leveraging the functional interaction between circRNAs and signaling pathways in CVD precision medicine.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"28 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134593","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":"Periventricular gradient of normal-appearing white matter in normal aging and multiple neurological diseases","authors":"Zhizheng Zhuo, Xiaolu Xu, Decai Tian, Runzhi Li, Yutong Bai, Yulu Shi, Siyao Xu, Shan Lv, Guanmei Cao, Geli Hu, Jun Xu, Jianguo Zhang, Fu-Dong Shi, Declan Chard, Frederik Barkhof, Sven Haller, Xinghu Zhang, Yunyun Duan, Yaou Liu","doi":"10.1016/j.jare.2025.08.059","DOIUrl":"https://doi.org/10.1016/j.jare.2025.08.059","url":null,"abstract":"<h3>Introduction</h3>A potential inflammation-associated periventricular gradient of normal-appearing white matter (NAWM) abnormalities has been identified in multiple sclerosis, but its presence in normal aging and other neurological diseases remains unclear.<h3>Objectives</h3>We aimed to determine whether a periventricular gradient of NAWM abnormalities occurs in normal aging and other neurological diseases.<h3>Methods</h3>A total of 290 Alzheimer’s disease, 262 Parkinson’s disease, 154 cerebral small vessel disease, 212 multiple sclerosis, as well as 344 younger healthy controls (HCs), 344 middle-aged HCs, and 398 older HCs with available MR diffusion images were included in this study. The periventricular gradient (the slope of regression model) in NAWM of normalized neurite density (NDI) and orientation dispersion indices (ODI), derived from diffusion MRI, was calculated using linear mixed models. Its associations with other MRI measures, clinical variables, and brain-wide gene expression were analyzed. Additional sensitivity and replication analyses were conducted.<h3>Results</h3>The periventricular gradients of both normalized NDI and ODI were observed in older HCs and all neurological disease groups. Such periventricular gradients play mediating roles between choroid plexus volume (a marker of neuroinflammation) and NAWM NDI or ODI, white matter hyperintensity volume, white and gray matter volumes, especially in neurological diseases. They exhibited both direct and indirect associations with cognitive and physical performance in normal aging and multiple neurological diseases. We observed correlations between periventricular gradients and underlying inflammatory, endothelial and synaptic gene expression. Sensitivity and replication analyses confirmed the main findings.<h3>Conclusion</h3>Clinically relevant periventricular gradients in tissue diffusion characteristics occur in normal aging and multiple neurological diseases, and share some underlying pathological mechanisms.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"8 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134596","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":"Global, regional, and national burden of cardiovascular diseases among postmenopausal women, 1990–2040: a systematic analysis for the global burden of disease study 2021","authors":"Shuangfei Xu, Shang Jia, Shaoqiang Yang, Delong Li, Ejuan Zhang, Fang Lei, Meng-Liu Zeng, Lijin Lin","doi":"10.1016/j.jare.2025.09.039","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.039","url":null,"abstract":"<h3>Background</h3>Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide. In postmenopausal women, physiological changes and hormonal transitions accelerate cardiovascular risk, yet global, sex-specific evidence for this group remains limited. Understanding their burden is essential to address biological vulnerabilities and structural inequities.<h3>Aim of review</h3>This review provides the first comprehensive global, regional, and national assessment of CVD burden among women aged ≥ 55 years from 1990 to 2021 and projects trends to 2040. It synthesizes epidemiological patterns, socio-demographic disparities, and major modifiable risk factors, with the goal of informing gender-sensitive and equity-oriented cardiovascular prevention and policy strategies.<h3>Key scientific concepts of review</h3>Data were obtained from the Global Burden of Disease (GBD) Study 2021, encompassing 204 countries and territories. Incidence, prevalence, mortality, and disability-adjusted life years (DALYs) were analyzed using age-standardized rates (ASRs). Temporal trends were quantified with estimated annual percentage changes (EAPCs), and decomposition analysis identified demographic (population growth, aging) and epidemiological contributions. Inequalities were evaluated using slope and concentration indices across socio-demographic index (SDI) levels. Bayesian age–period–cohort models were applied to forecast CVD burden through 2040. Key findings indicate that although ASIR and ASMR declined globally, absolute CVD cases and deaths nearly doubled due to demographic expansion. Disparities widened: high-SDI regions achieved the steepest reductions, while low-SDI regions showed slower progress or worsening trends. Ischemic heart disease and stroke remained the dominant contributors, endocarditis was the fastest-rising subtype, and high systolic blood pressure consistently emerged as the leading modifiable risk factor. Collectively, these findings highlight a growing and uneven burden of CVD in postmenopausal women. Strengthened hypertension control, integrated prevention strategies, and investment in primary healthcare—particularly in low-SDI settings—are urgently needed. This review provides a woman-centered evidence base to support equitable cardiovascular health policy and resource allocation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"28 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134511","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":"Roles of Msx2 in exogen control: modulating the stem cell niche during the transition from hair shedding to regeneration","authors":"Qi Chen, Wen-Chien Jea, Ting-Xin Jiang, Ping Wu, Chi Zhang, Ji Li, Mingxing Lei, Cheng-Ming Chuong, Ya-Chen Liang","doi":"10.1016/j.jare.2025.09.040","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.040","url":null,"abstract":"<h3>Introduction</h3>The exogen phase of the hair follicle cycle, during which club hairs are shed and new hairs emerge, represents a critical transitional step involving distinct structural remodeling and adhesive changes. Despite its fundamental importance, the molecular mechanisms orchestrating exogen remain largely unknown.<h3>Objective</h3>To investigate the role of Msx2 in regulating hair anchoring, hair follicle stem cell (HFSC) lineage commitment, and extracellular matrix (ECM) remodeling during exogen.<h3>Methods</h3>We employed <em>Msx2</em>-knockout (KO) mice, bulk RNA sequencing, and late exogen transcriptome comparisons to identify differentially expressed genes (DEGs) and disrupted pathways. Additionally, protein interaction assays were conducted for functional studies.<h3>Results</h3><em>Msx2</em> deficiency mice still form new bulges containing HFSCs for subsequent hair cycles, but this resulted in the failed anchoring of older bulges and club hairs, leading to aberrant hair retention and accelerated hair shedding. Transcriptomic analysis revealed widespread transcriptional reprogramming, particularly in ECM-related genes, with significant overlap between <em>Msx2</em>-KO HFSCs and late exogen DEGs. <em>Msx2</em>-KO mice exhibited downregulated adhesion molecules, disrupted HFSC niche integrity, increased keratinization, and aberrant differentiation in HFSC and hair germ cells. Mechanistically, MSX2 directly interacts with SMAD proteins to regulate TGF-β signaling, thereby modulating ECM gene expression and suppressing HFSC trans-epidermal differentiation.<h3>Conclusions</h3>Our findings establish <em>Msx2</em> as a master regulator of exogen control, orchestrating hair shedding, HFSC niche stability, and ECM remodeling. This study provides new insights into hair follicle cycling dynamics and identifies Msx2 as a potential therapeutic target for promoting hair regeneration and mitigating alopecia phenotypes.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"37 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127700","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":"Disphosphate based hydrogel microspheres for targeted transarterial radioembolization and chemoembolization therapies","authors":"Xuexiao Li, Binyan Zhong, Nan Jiang, Jintao Huang, Di Hu, Ruoran Zhou, Jianfeng Zeng, Wenmiao Shu, Guangxin Duan, Shuwang Wu, Ling Wen","doi":"10.1016/j.jare.2025.09.044","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.044","url":null,"abstract":"<h3>Introduction</h3>Transarterial radioembolization (TARE) is a highly effective treatment for unresectable hepatocellular carcinoma (HCC). However, current clinically available radioactive ⁹⁰Y resin microspheres face significant challenges such as isotope leakage and low specific activity, compromising the safety and therapeutic efficacy.<h3>Objectives</h3>To address these challenges, we propose a novel diphosphonate based hydrogel microspheres (DPMs) for safer and more effective TARE therapies. The diphosphonate have a strong chelating capability with various metal ions which provide a universal strategy for tightly labelling the hydrogel microsphere with different therapeutic metal nuclides.<h3>Methods</h3>In this study, DPMs were fabricated via microfluidic technology, followed by ¹⁷⁷Lu radiolabeling and doxorubicin (DOX) loading. Physicochemical characterization, radiostability assays, and dual-modality therapeutic efficacy were systematically evaluated in vitro and in orthotopic HCC rabbit models, with biosafety validated through histopathology and serum biochemistry.<h3>Results</h3>DPMs achieved a labeling efficiency of 98.3 % within 15 min. Meanwhile, the radiolabeling rate maintained 99 % over 7 days in a 10 % fetal bovine serum solution, demonstrating exceptional radiostabilty. The high in vitro radiostability is also consistent with in vivo experiments. Additionally, the porous structure of DPMs enables high loading and controlled release of chemotherapeutic drugs, making the hydrogel microspheres also the ideal carriers for transcatheter arterial chemoembolization (TACE). By combining TARE and TACE, we have developed a novel ¹⁷⁷Lu-DPMs@DOX platform, exhibiting remarkable therapeutic performance against HCC without any observed side effect.<h3>Conclusion</h3>This study introduces a groundbreaking approach using highly effective diphosphonate based microspheres to deliver precise, safe, and powerful treatment for unresectable HCC and other challenging tumors","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"7 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117010","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":"Bisphenol S drives breast cancer metastasis by inhibiting dopamine receptor D2 to activate the Akt/GSK3β oncogenic axis","authors":"Sicheng Liu, Ping Deng, Chengmeng Liu, Huihui Hong, Qixue Zheng, Jinxian Lin, Jiayi Li, Zhulin Du, Lingling Yang, Kun Luo, Haiyan Yu, Zhengwei Liang, Zhengping Yu, Huifeng Pi, Zhou Zhou","doi":"10.1016/j.jare.2025.09.045","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.045","url":null,"abstract":"<h3>Introduction</h3>Bisphenol S (BPS), a substitute for bisphenol A (BPA), serves as an endocrine disruptor implicated in breast cancer (BC) progression, but its mechanisms remain unclear.<h3>Objectives</h3>This study aimed to elucidate the underlying mechanisms of BPS effects on BC metastasis through <em>in vivo</em> and <em>in vitro</em> experiments.<h3>Methods</h3>Transgenic MMTV-Erbb2 mice that spontaneously developed breast tumors were orally administered BPS (50 μg/L) for 19 weeks, and BC cells were exposed to BPS (0, 0.01, 0.1, or 1 μM) for 72 h to examine the effects of BPS exposure on the migration and invasion of BC cells. Furthermore, we employed transcriptomics, KEGG enrichment analysis and Comparative Toxicogenomics Database (CTD) predictions to explore the potential mechanisms underlying BPS −induced BC metastasis. In addition, we used tissue microarray (TMA) and public databases to reveal DRD2′s critical role in BC progression.<h3>Results</h3>Our results indicated that low-dose BPS (50 μg/L, approximately 6.14 μg/kg/day) facilitated BC metastasis both <em>in vitro</em> and <em>in vivo</em>. Transcriptomic analysis identified DRD2 as a critical regulator of migration and invasion in BPS-exposed MCF-7 cells. Furthermore, KEGG enrichment analysis coupled with the CTD demonstrated that BPS enhanced the migration and invasion of BC cells via the Akt/GSK3β signaling pathway activation. Importantly, DRD2 overexpression apparently blocked the Akt/GSK3β pathway, effectively reversing BPS-induced metastasis of BC both <em>in vitro</em> and <em>in vivo</em>. Intriguingly, TMA and public database analyses revealed a marked decrease of DRD2 levels in BC tissues, which were inversely correlated with p-Akt levels in BC tissues and positively associated with the poor clinical characteristics of BC patients.<h3>Conclusion</h3>BPS exposure reduces DRD2 levels, activating Akt/GSK3β signaling to drive BC metastasis. These findings highlight the risk of BPS as a BPA alternative and unravel mechanistic insights into the role of environmental endocrine disruptors in cancer progression.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"89 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117008","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":"Olfactory–gustatory cross-modal integration: mechanisms of aroma-induced sweetness enhancement, sensory evaluation methodologies, neuroimaging evidence and advances in influencing factors","authors":"Yanli Tan, Xueli Pang","doi":"10.1016/j.jare.2025.09.043","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.043","url":null,"abstract":"<h3>Background</h3>Excessive sugar intake induces health issues such as excess energy, obesity and cardiovascular diseases. Reducing sugar consumption has become a global consensus; however, achieving this without compromising flavour perception remains a major challenge. Previous studies have highlighted the potential risks associated with non-nutritive sweeteners, and novel measures for sugar reduction, such as modifying sweetener ratios and enzymatic conversion, are limited in scope. In-depth studies have revealed that aroma-induced sweetness enhancement is a promising alternative for reducing sugar consumption without compromising perceived sweetness, enabling a healthy way of enjoying sweet flavours<h3>Aim of review</h3>By systematically sorting out current knowledge on the mechanism of action, evaluation approaches, and influencing factors of aroma-induced sweetness enhancement, and revealing the cross-modal interaction mechanism between aroma and taste, this study aims to provide a theoretical framework for advancing research on multisensory flavor perception. Furthermore, it underscores the potential of the interdisciplinary integration of neurosensory science and food science to inform the design of flavor optimization strategies for low-sugar products, thereby contributing to healthier dietary solutions for targeted populations.<h3>Key scientific concepts of review</h3>Herein, the physiological basis of taste and smell and their perceptual pathways are systematically reviewed, and the neural and psychological factors of olfactory–gustatory synergy are investigated. In addition, this review summarises the sensory evaluation methods and neuroimaging techniques to assess the sweetening effects of aroma. Moreover, it discusses various factors influencing aroma-induced sweetness enhancement, including the physical properties of food, eating environment, individual differences in consumers and oral processing. Aroma-based sweetening has great potential for sugar reduction without compromising sweetness, and future in-depth research requires interdisciplinary cooperation covering multiple dimensions such as molecular mechanisms, personalisation techniques, ingredient screening, stability optimisation, evaluation method innovation and health regulation adaptation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"8 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117009","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":"Advances in physical and chemical strategies for dentin hypersensitivity therapy","authors":"Xinru Li, Qihui Wang, Yirong Sun, Guoliang Wang, Congxiao Zhang, Jianxun Ding","doi":"10.1016/j.jare.2025.09.041","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.041","url":null,"abstract":"<h3>Background</h3>Dentin hypersensitivity (DH) is a prevalent and acute dental pain disorder marked by a brief yet sharp toothache caused by exposed dentin, often in response to thermal, chemical, and mechanical stimuli. It significantly affects a person’s quality of life, interfering with routine activities, such as eating and drinking. With an improved understanding of the mechanisms underlying DH, various physical and chemical strategies have been developed to alleviate the condition.<h3>Aim of the review</h3>This review evaluates three principal mechanistic theories underlying DH desensitization, including the Direct Innervation Hypothesis, the Odontoblast Receptor Theory, and the Hydrodynamic Theory. It provides a detailed analysis of current physical, chemical, and synergistic therapeutic methods used for desensitization. Additionally, it discusses potential future therapeutic approaches for the treatment of DH.<h3>Key scientific concepts of review</h3>This review highlights recent advancements and ongoing challenges in applying physical and chemical strategies for DH treatment. It also discusses potential future strategies and methods, offering insights into the prospects for the field.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"40 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117011","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":"Development and clinical validation of a novel protein biomarkers-based algorithm for risk prediction and diagnosis of advanced liver fibrosis: a multi-centre study","authors":"Chloe Yu-Yan Cheung, Pei Wan, Heng Wan, Chenxin Xu, Xi Jia, Carol Ho-Yi Fong, David Tak-Wai Lui, Erfei Song, Xingying Chen, Wing-Sun Chow, Yu-Cho Woo, Kathryn Choon-Beng Tan, Wai-Kay Seto, Cunchuan Wang, Jie Shen, Karen Siu-Ling Lam, Chi-Ho Lee, Aimin Xu","doi":"10.1016/j.jare.2025.09.033","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.033","url":null,"abstract":"<h3>Introduction</h3>Type 2 diabetes (T2D) and obesity contribute significantly to the elevated risk of liver fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). However, there is a lack of reliable and cost-effective non-invasive test (NIT) for detecting liver fibrosis in T2D/obese individuals.<h3>Objectives</h3>This study aimed to develop a simple biomarker-based algorithm for detecting advanced liver fibrosis among T2D/obesity subjects with MASLD and to validate its diagnostic performance in both clinic- and community-based cohorts.<h3>Methods</h3>Diagnostic performances of circulating thrombospondin-2 (TSP2), a novel fibrosis marker, and the three individual components of Enhanced Liver Fibrosis (ELF) test were evaluated in three independent cohorts. These included a clinic-based derivation cohort (N = 846) and a community-based validation cohort (N = 803), both comprising of T2D patients with vibration-controlled transient elastography (VCTE)-diagnosed MASLD. Additionally, a clinic-based validation cohort of morbidly-obese patients with biopsy-proven MASLD (N = 223) was included. An algorithm (TaP score) based on <u>T</u>SP2 <u>a</u>nd <u>p</u>rocollagen 3 N-terminal peptide (PIIINP), a component of ELF, was constructed from the multivariate logistic regression model and compared with existing NITs, including ELF, fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS). The dual-cut-off approach was used to define the rule-in and rule-out cut-offs.<h3>Results</h3>Circulating TSP2 (AUC[95 %CI]:0.844[0.810–0.878]) and PIIINP (AUC[95 %CI]:0.843(0.807–0.875]) showed excellent diagnostic performance and were used to construct the biomarker-based algorithm. The TaP score (AUC[95 %CI]:0.900[0.874–0.925]) significantly outperformed ELF (AUC[95 %CI]:0.809[0.773–0.843]), FIB-4 (AUC[95 %CI]:0.597[0.544–0.647]) and NFS (AUC[95 %CI]:0.585[0.528–0.639]) (all DeLong P &lt; 0.001), showing high specificity (85.16 %), sensitivity (78.62 %), and negative predictive value (NPV) (95.08 %) at the optimal cut-off. This algorithm resulted in fewer patients with indeterminate results compared to ELF. Its diagnostic performance in the two external validation cohorts was comparable to that in the derivation cohort.<h3>Conclusions</h3>The TaP score demonstrated good diagnostic ability with generally better performance compared to ELF, and had the potential to be developed as a novel NIT.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"10 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116596","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":"Orthosteric–allosteric dual inhibitors of PI5P4Kγ with potent antitumor activity in non-small cell lung cancer","authors":"Liang Xiong, Lei Tang (唐磊), Wenfeng Zhao, Rongtao Wang, Cheng Cheng, Daoping Wang, Yechun Xu, Lei Tang (汤磊), Yanhua Fan","doi":"10.1016/j.jare.2025.09.024","DOIUrl":"https://doi.org/10.1016/j.jare.2025.09.024","url":null,"abstract":"<h3>Introduction</h3>Phosphatidylinositol 5-phosphate 4-kinase type II gamma (PI5P4Kγ) has emerged as a promising therapeutic target in oncology due to its key role in cancer progression. However, currently available inhibitors targeting either the orthosteric or allosteric sites of PI5P4Kγ suffer from limited <em>in vitro</em> activity and in vivo validation.<h3>Objectives</h3>This study aimed to develop a highly potent and selective PI5P4Kγ inhibitor capable of simultaneously engaging both the orthosteric and allosteric sites, as well as to validate their potential in therapy for non-small cell lung cancer (NSCLC) were investigated.<h3>Methods</h3>Through the structural modification of the propionamide side chain of the pyridine ring and the N3 substituent of the quinazolinone, the structure–activity relationship (SAR) was elucidated, leading to the identification of the target compound <strong>n40</strong>. The binding mode of <strong>n40</strong> to PI5P4Kγ, was elucidated by X-ray crystallography. <em>In vitro</em> effects were assessed through KINOMEscan Technology, cell proliferation, apoptosis, and EMT analysis. In vivo efficacy was evaluated using an HCC827 xenograft mouse model. Both single-dose (up to 400 mg/kg) and repeated-dose (20–180 mg/kg/day for 28 days) toxicity studies of <strong>n40</strong> were conducted in C57BL/6 mice, with comprehensive monitoring of physiological parameters and organ toxicity indices.<h3>Results</h3>Compound <strong>n40</strong> exhibited a strong binding affinity for PI5P4Kγ (<em>K</em>_d = 6.55 nM), with 3,000-fold selectivity over other two isoforms. Additionally, it displayed sub-50 nM antiproliferative activity in NSCLC cells with higher PI5P4Kγ levels. X-ray crystallography revealed <strong>n40</strong> simultaneously binds to both orthosteric and a novel<!-- --> <!-- -->allosteric pocket. Functionally, <strong>n40</strong> induced S-phase arrest, apoptosis, and EMT reversal and PI3K/AKT signaling inhibition in a PI5P4Kγ-dependent manner. In HCC827 xenografts, <strong>n40</strong> achieved &gt; 60 % tumor growth inhibition without any observed toxicity.<h3>Conclusion</h3>This study establishes PI5P4Kγ as a druggable target in NSCLC and demonstrates that dual orthosteric–allosteric targeting is a viable strategy to achieve potent and selective PI5P4Kγ inhibitors.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"61 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145116597","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}