Oxaliplatin is a first-line chemotherapeutic agent for cancer treatment, but the monotherapy effect is limited.Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a dose-limiting clinical problem, leading to decreased quality of life or even treatment discontinuation. Fibroblast growth factor 1 (FGF1) was initially identified in the pituitary gland and the brain as a substance that promotes mitosis in fibroblasts, however, dysregulated FGF1 expression is associated with human pathologies, particularly cancer.
{"title":"Targeting the FGF1/FGFR signaling pathway enhances the antitumor effect of oxaliplatin and alleviates chemotherapy-induced peripheral neuropathy","authors":"Cuiqing Xie, Zhiqi Li, Jinlan Cao, Yuna Cheng, Zhaohui Jin, Youfeng Ge, Junhui Deng, Zhihua Luo, Chenyang Zheng, Lili Hou, Guoyu Zhang, Jie Niu, Dong Fang","doi":"10.1016/j.jare.2026.02.005","DOIUrl":"https://doi.org/10.1016/j.jare.2026.02.005","url":null,"abstract":"Oxaliplatin is a first-line chemotherapeutic agent for cancer treatment, but the monotherapy effect is limited.<ce:hsp sp=\"0.25\"></ce:hsp>Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a dose-limiting clinical problem, leading to decreased quality of life or even treatment discontinuation. Fibroblast growth factor 1 (FGF1) was initially identified in the pituitary gland and the brain as a substance that promotes mitosis in fibroblasts, however, dysregulated FGF1 expression is associated with human pathologies, particularly cancer.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"244 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146320","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}
Pub Date : 2026-02-09DOI: 10.1016/j.jare.2026.02.003
Lushan Xiao, Jiaren Wang, Hao Cui, Hongbo Zhu, Jingzhe He, Huangying Deng, Wenfeng Zhang, Hanzhi Dong, Yundong Zhou, Pu Jiang, Lin Zeng, Jie Peng, Peishuang Xu, Ruozheng Shen, Nazakat Kurban, Manxun Lin, Shaodong Lu, Xie Weng, Chang Hong, Li Liu
Background
Immunotherapy effectively extends survival in hepatocellular carcinoma (HCC) patients. Predicting immunotherapy responses can inform treatment strategies for HCC. This study aimed to develop multi-modal transformer-based models to predict the immunotherapy response and to validate their performance in an independent cohort.
Materials and methods
Patients with HCC from five medical centers were retrospectively included. Clinical features were selected using Least Absolute Shrinkage and Selection Operator method. Multi-modal gradual fusion transformer-based models were trained using clinical features and intra- and peritumoral patches from arterial and portal venous phase computed tomography images in the training cohort. These models were tested on internal validation and external test cohorts. Models’ performance and generalization across different modalities were compared.
Results
Patients from the Hospital 1 were partitioned into a training (n = 209) and an internal validation cohort (n = 90) at a 7:3 ratio. And patients from the other four centers formed an independent external test cohort (n = 85). The number of progressive disease (PD) patients in the training, internal validation, and external test cohorts was 44 (21.1%), 20 (22.2%), and 20 (23.5%), respectively. The model using clinical data, intratumoral imaging, and peritumoral imaging modalities (GIFT-CIP) demonstrated strong predictive performance, achieving an area under the curve (AUC) values of 0.926 (95% CI: 0.892–0.962), 0.911 (95% CI: 0.878–0.946), and 0.883 (95% CI: 0.835–0.935) for training cohort, internal validation cohort, and external test cohort, respectively. Crucially, the GIFT-CIP model effectively stratified patients into low- and high-risk groups, showing significant differences in progression-free survival and overall survival in external test cohort (p < 0.01).
Conclusions
The GIFT-CIP model is a non-invasive method for predicting immunotherapy responses in patients with HCC. This model may be clinically useful for assisting clinicians in guiding surveillance follow-up and identifying optimal immunotherapy strategies.
{"title":"Multi-modal gradual fusion transformer-based model for predicting immunotherapy response in patients with hepatocellular carcinoma","authors":"Lushan Xiao, Jiaren Wang, Hao Cui, Hongbo Zhu, Jingzhe He, Huangying Deng, Wenfeng Zhang, Hanzhi Dong, Yundong Zhou, Pu Jiang, Lin Zeng, Jie Peng, Peishuang Xu, Ruozheng Shen, Nazakat Kurban, Manxun Lin, Shaodong Lu, Xie Weng, Chang Hong, Li Liu","doi":"10.1016/j.jare.2026.02.003","DOIUrl":"https://doi.org/10.1016/j.jare.2026.02.003","url":null,"abstract":"<h3>Background</h3>Immunotherapy effectively extends survival in hepatocellular carcinoma (HCC) patients. Predicting immunotherapy responses can inform treatment strategies for HCC. This study aimed to develop multi-modal transformer-based models to predict the immunotherapy response and to validate their performance in an independent cohort.<h3>Materials and methods</h3>Patients with HCC from five medical centers were retrospectively included. Clinical features were selected using Least Absolute Shrinkage and Selection Operator method. Multi-modal gradual fusion transformer-based models were trained using clinical features and intra- and peritumoral patches from arterial and portal venous phase computed tomography images in the training cohort. These models were tested on internal validation and external test cohorts. Models’ performance and generalization across different modalities were compared.<h3>Results</h3>Patients from the Hospital 1 were partitioned into a training (n = 209) and an internal validation cohort (n = 90) at a 7:3 ratio. And patients from the other four centers formed an independent external test cohort (n = 85). The number of progressive disease (PD) patients in the training, internal validation, and external test cohorts was 44 (21.1%), 20 (22.2%), and 20 (23.5%), respectively. The model using clinical data, intratumoral imaging, and peritumoral imaging modalities (GIFT-CIP) demonstrated strong predictive performance, achieving an area under the curve (AUC) values of 0.926 (95% CI: 0.892–0.962), 0.911 (95% CI: 0.878–0.946), and 0.883 (95% CI: 0.835–0.935) for training cohort, internal validation cohort, and external test cohort, respectively. Crucially, the GIFT-CIP model effectively stratified patients into low- and high-risk groups, showing significant differences in progression-free survival and overall survival in external test cohort (p < 0.01).<h3>Conclusions</h3>The GIFT-CIP model is a non-invasive method for predicting immunotherapy responses in patients with HCC. This model may be clinically useful for assisting clinicians in guiding surveillance follow-up and identifying optimal immunotherapy strategies.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"93 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146175","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}
Pub Date : 2026-02-09DOI: 10.1016/j.jare.2026.02.008
Xuewei Yang, Meichen Zhu, Lirong Zhu, Xiaoli Li, Meihua Xie, Yi Chen, Ke-Qin Zhang, Jinkui Yang
Serine/threonine kinases (STKs) are crucial for contribute to the growth, pathogenicity, and potassium homeostasis in filamentous fungal pathogens. However, the functions of STK in hyphal fusion, trap morphogenesis, and lifestyle transitions of nematode-trapping (NT) fungi remain unclear.
{"title":"AoHal4b interacts with AoAdv-1 governs hyphal fusion, nematode predation ability, and secondary metabolism in Arthrobotrys oligospora","authors":"Xuewei Yang, Meichen Zhu, Lirong Zhu, Xiaoli Li, Meihua Xie, Yi Chen, Ke-Qin Zhang, Jinkui Yang","doi":"10.1016/j.jare.2026.02.008","DOIUrl":"https://doi.org/10.1016/j.jare.2026.02.008","url":null,"abstract":"Serine/threonine kinases (STKs) are crucial for contribute to the growth, pathogenicity, and potassium homeostasis in filamentous fungal pathogens. However, the functions of STK in hyphal fusion, trap morphogenesis, and lifestyle transitions of nematode-trapping (NT) fungi remain unclear.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"6 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146321","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}
Pub Date : 2026-02-08DOI: 10.1016/j.jare.2026.02.004
Huiyu Hou, Xiangjin Kong, Jiaqi Xiao, Guoxiang Jiang, Hong Zhu, Yueming Jiang, Hongxia Qu, Taotao Li
Significant progress has been made in uncovering the role of DNA methylation in the development and ripening of fruit. However, whether DNA methylation is involved in litchi fruit ripening and in the corresponding mechanisms remain unknown.
{"title":"An increase in DNA methylation contributes to anthocyanin biosynthesis in the pericarp as litchi (Litchi chinensis Sonn.) fruit ripens","authors":"Huiyu Hou, Xiangjin Kong, Jiaqi Xiao, Guoxiang Jiang, Hong Zhu, Yueming Jiang, Hongxia Qu, Taotao Li","doi":"10.1016/j.jare.2026.02.004","DOIUrl":"https://doi.org/10.1016/j.jare.2026.02.004","url":null,"abstract":"Significant progress has been made in uncovering the role of DNA methylation in the development and ripening of fruit. However, whether DNA methylation is involved in litchi fruit ripening and in the corresponding mechanisms remain unknown.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"34 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146146323","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}
Pub Date : 2026-02-05DOI: 10.1016/j.jare.2026.01.085
Qing Lv, Maoping Shao, Mingyan Li, Mengxian Long, Guoqing Pan
Background
Microsporidia are a class of obligate intracellular parasitic unicellular eukaryotes that infect almost all animals. Under appropriate environmental stimuli, microsporidia transport the sporoplasm into the host cell through the releasing polar tube (PT), thereby completing the infection process. The sporoplasm is the initial cell of infection and proliferation of microsporidia.
Aim of review
Recent studies on the sporoplasm have achieved significant advances. For example, cryo-electron microscopy (Cryo-EM) elucidated the sporoplasm formation process, while single-cell RNA sequencing characterized microsporidia gene expression across developmental stages. In this review, we summarize the structural characteristics of the sporoplasm and provide a detailed discussion on the gene expression features and functions during the sporoplasm stage. Additionally, we outline the interactions of sporoplasm during infection, as well as the in vitro cultivation of the sporoplasm of Nosema bombycis (N. bombycis), which lays the foundation for understanding the infection mechanism of microsporidia and the establishment of a complete genetic manipulation system.
Key scientific concepts of review
We review and discuss recent research progress on the sporoplasm, particularly conducting in-depth comparative analyses of the biological characteristics of different microsporidia sporoplasm and gene expression patterns across various developmental stages. On this basis, we propose the main directions and research roadmap for future studies, including structural biology, host-parasite molecular interaction, and genetic engineering feasibility. These studies will contribute to elucidating the molecular mechanisms of microsporidia life cycle and pathogenesis.
微孢子虫是一类专性细胞内寄生的单细胞真核生物，几乎可以感染所有动物。在适当的环境刺激下，微孢子虫通过释放极管（PT）将孢子质转运到宿主细胞内，从而完成感染过程。孢子质是微孢子虫感染和增殖的初始细胞。近年来对孢子质的研究取得了重大进展。例如，低温电子显微镜（Cryo-EM）阐明了孢子质形成过程，而单细胞RNA测序表征了微孢子虫基因在发育阶段的表达。本文综述了孢子质的结构特征，并对孢子质阶段基因的表达特征和功能进行了详细的讨论。此外，我们还概述了侵染过程中孢子质之间的相互作用，以及家蚕微孢子虫（Nosema bombycis， N. bombycis）孢子质的体外培养，为了解微孢子虫侵染机制和建立完整的遗传操作体系奠定基础。综述和讨论了近年来关于孢子质的研究进展，特别是对不同微孢子虫孢子质的生物学特性和不同发育阶段的基因表达模式进行了深入的比较分析。在此基础上，我们提出了未来研究的主要方向和研究路线图，包括结构生物学、宿主-寄生虫分子相互作用和基因工程可行性。这些研究将有助于阐明微孢子虫生命周期和发病机制的分子机制。
{"title":"Sporoplasm: The initial cell in microsporidia life cycle","authors":"Qing Lv, Maoping Shao, Mingyan Li, Mengxian Long, Guoqing Pan","doi":"10.1016/j.jare.2026.01.085","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.085","url":null,"abstract":"<h3>Background</h3>Microsporidia are a class of obligate intracellular parasitic unicellular eukaryotes that infect almost all animals. Under appropriate environmental stimuli, microsporidia transport the sporoplasm into the host cell through the releasing polar tube (PT), thereby completing the infection process. The sporoplasm is the initial cell of infection and proliferation of microsporidia.<h3>Aim of review</h3>Recent studies on the sporoplasm have achieved significant advances. For example, cryo-electron microscopy (Cryo-EM) elucidated the sporoplasm formation process, while single-cell RNA sequencing characterized microsporidia gene expression across developmental stages. In this review, we summarize the structural characteristics of the sporoplasm and provide a detailed discussion on the gene expression features and functions during the sporoplasm stage. Additionally, we outline the interactions of sporoplasm during infection, as well as the <em>in vitro</em> cultivation of the sporoplasm of <em>Nosema bombycis</em> (<em>N. bombycis</em>), which lays the foundation for understanding the infection mechanism of microsporidia and the establishment of a complete genetic manipulation system.<h3>Key scientific concepts of review</h3>We review and discuss recent research progress on the sporoplasm, particularly conducting in-depth comparative analyses of the biological characteristics of different microsporidia sporoplasm and gene expression patterns across various developmental stages. On this basis, we propose the main directions and research roadmap for future studies, including structural biology, host-parasite molecular interaction, and genetic engineering feasibility. These studies will contribute to elucidating the molecular mechanisms of microsporidia life cycle and pathogenesis.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"45 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146135067","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}
Sarcopenia, characterized by the progressive age-related loss of skeletal muscle mass and function, is a primary driver of ambulatory dysfunction in older adults and lacks approved therapeutics. Although exercise has been shown to mitigate muscle aging through activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-dependent mitochondrial biogenesis and oxidative metabolism, the practical implementation of exercise regimens is often constrained by age-related physical frailty and declining mobility. This limitation underscores the need for pharmacological approaches to replicate these advantageous adaptations.
Objectives
This study aimed to identify a potential therapeutic candidate that mimic the beneficial effects of PGC-1α overexpression and exercise intervention on aging-related sarcopenia and mitochondrial dysfunction.
Methods
We analyzed age-stratified muscle transcriptome data from various species and assessed the effects of muscle-specific PGC-1α overexpression on muscle aging. In silico transcriptome-based drug screening was conducted using the Connectivity Map (CMap). Subsequently, C2C12 myoblasts, young mice, aged Caenorhabditis elegans (C. elegans), and D-galactose (D-gal)-induced accelerated aging mice were administrated with celastrol to validate its therapeutic effect in counteracting aging-related muscle wasting and mitochondrial dysfunction. Celastrol’s efficacy and mechanisms were assessed through histological analysis, molecular biology, and transcriptomics analysis.
Results
Celastrol, a bioactive triterpenoid from Tripterygium wilfordii Hook. F., was identified as a top candidate that mimicked the gene signature induced by PGC-1α overexpression or exercise. Celastrol potentiated myogenic differentiation and mitochondrial bioenergetic capacity in vitro and in vivo with no side effects. In C. elegans, celastrol extended lifespan by 27.6% at 10 μM, concurrently reducing aging markers while restoring muscle integrity and mitochondrial morphology. Administration of celastrol also ameliorated aging-related muscle decline through boosting myogenic differentiation and mitochondrial oxidative metabolism in accelerated aging mice.
Conclusion
Collectively, these findings suggest celastrol as a pharmacological mimetic of exercise-induced mitochondrial rejuvenation, offering a translatable strategy to combat age-related muscle decline.
{"title":"In silico transcriptome-based drug screening identifies celastrol as a multi-species therapeutic agent against aging-related sarcopenia and mitochondrial dysfunction","authors":"Bangfu Wu, Jiaxin Liu, Zhaoyu Cui, Xingzhu Yin, Li Mo, Li Chen, Huimin Chen, Xuer Cheng, Yu Wang, Fangqu Liu, Chanhua Liang, Yuna Tian, Yuxia Chen, Xiaocui Liu, Yanyan Li, Ping Yao, Chao Gao, Yuhan Tang","doi":"10.1016/j.jare.2026.01.079","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.079","url":null,"abstract":"<h3>Introduction</h3>Sarcopenia, characterized by the progressive age-related loss of skeletal muscle mass and function, is a primary driver of ambulatory dysfunction in older adults and lacks approved therapeutics. Although exercise has been shown to mitigate muscle aging through activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-dependent mitochondrial biogenesis and oxidative metabolism, the practical implementation of exercise regimens is often constrained by age-related physical frailty and declining mobility. This limitation underscores the need for pharmacological approaches to replicate these advantageous adaptations.<h3>Objectives</h3>This study aimed to identify a potential therapeutic candidate that mimic the beneficial effects of PGC-1α overexpression and exercise intervention on aging-related sarcopenia and mitochondrial dysfunction.<h3>Methods</h3>We analyzed age-stratified muscle transcriptome data<!-- --> <!-- -->from various species and assessed the effects of muscle-specific PGC-1α overexpression on muscle aging. <em>In silico</em> transcriptome-based drug screening was conducted using the Connectivity Map (CMap). Subsequently, C2C12 myoblasts, young mice, aged <em>Caenorhabditis elegans</em> (<em>C. elegans</em>), and D-galactose (D-gal)-induced accelerated aging mice were administrated with celastrol to validate its therapeutic effect in counteracting aging-related muscle wasting and mitochondrial dysfunction. Celastrol’s efficacy and mechanisms were assessed through histological analysis, molecular biology, and transcriptomics analysis.<h3>Results</h3>Celastrol, a bioactive triterpenoid from <em>Tripterygium wilfordii Hook. F.,</em> was identified as a top candidate that mimicked the gene signature induced by PGC-1α overexpression or exercise. Celastrol potentiated myogenic differentiation and mitochondrial bioenergetic capacity <em>in vitro</em> and <em>in vivo</em> with no side effects. In <em>C. elegans,</em> celastrol extended lifespan by 27.6% at 10 μM, concurrently reducing aging markers while restoring muscle integrity and mitochondrial morphology. Administration of celastrol also ameliorated aging-related muscle decline through boosting myogenic differentiation and mitochondrial oxidative metabolism in accelerated aging mice.<h3>Conclusion</h3>Collectively, these findings suggest celastrol as a<!-- --> <!-- -->pharmacological mimetic of exercise-induced mitochondrial rejuvenation, offering a translatable strategy to combat age-related muscle decline.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101868","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}
Pub Date : 2026-02-02DOI: 10.1016/j.jare.2026.01.070
Suling Xu, Haitao Yang, Boris Minev, Wenxue Ma
Personalized nanovaccines represent advancing frontier in cancer immunotherapy by integrating patient-specific tumor antigens with biomimetic delivery systems to enhance immune activation, targeting precision and clinical efficacy. Biomimetic platforms including exosome-, red blood cell (RBC)-, and immune cell membrane-coated nanoparticles, as well as artificial antigen-presenting cell (aAPC) systems, recreate native biological interfaces to improve antigen presentation, macrophage polarization, and adaptive immune priming. Despite significant progress, major translational challenges remain, including incomplete mechanistic understanding, regulatory complexity, and manufacturing scalability. This review synthesizes recent advances in biomimetic and personalized nanovaccine design, highlighting clinical progress in lipid nanoparticle (LNP)-based vaccines such as BNT111 and mRNA-4157, emerging innate immune adjuvants including Toll-like receptor (TLR) and stimulator of interferon genes (STING) agonists, and rational combination strategies with immune checkpoint blockade. Key safety and quality consideration including immunotoxicity, off-target immune activation, and batch heterogeneity are critically evaluated alongside emerging engineering solutions. Finally, future directions integrating AI-guided neoantigen prediction, modular microfluidic manufacturing, and multi-omic biomarker frameworks are discussed to accelerate next generation cancer nanovaccine translation.
{"title":"Biomimetic and personalized nanovaccines in cancer immunotherapy: Design innovations, translational challenges, and future directions","authors":"Suling Xu, Haitao Yang, Boris Minev, Wenxue Ma","doi":"10.1016/j.jare.2026.01.070","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.070","url":null,"abstract":"Personalized nanovaccines represent advancing frontier in cancer immunotherapy by integrating patient-specific tumor antigens with biomimetic delivery systems to enhance immune activation, targeting precision and clinical efficacy. Biomimetic platforms including exosome-, red blood cell (RBC)-, and immune cell membrane-coated nanoparticles, as well as artificial antigen-presenting cell (aAPC) systems, recreate native biological interfaces to improve antigen presentation, macrophage polarization, and adaptive immune priming. Despite significant progress, major translational challenges remain, including incomplete mechanistic understanding, regulatory complexity, and manufacturing scalability. This review synthesizes recent advances in biomimetic and personalized nanovaccine design, highlighting clinical progress in lipid nanoparticle (LNP)-based vaccines such as BNT111 and mRNA-4157, emerging innate immune adjuvants including Toll-like receptor (TLR) and stimulator of interferon genes (STING) agonists, and rational combination strategies with immune checkpoint blockade. Key safety and quality consideration including immunotoxicity, off-target immune activation, and batch heterogeneity are critically evaluated alongside emerging engineering solutions. Finally, future directions integrating AI-guided neoantigen prediction, modular microfluidic manufacturing, and multi-omic biomarker frameworks are discussed to accelerate next generation cancer nanovaccine translation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"97 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098396","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}
Obesity-associated non-alcoholic fatty liver disease (NAFLD) remains a global health burden with limited treatment options. Human milk fat substitutes (HMFS), designed to mimic the triacylglycerol structure of breast milk, have shown potential metabolic benefits. However, the mechanisms underlying their effects on hepatic lipid metabolism remain unclear.
Objectives
This study aims to evaluate the therapeutic effects of HMFS on established high fat diet-induced metabolic dysfunction and to delineate the lipid-mediated pathways involved.
Methods
A high-fat diet–induced obese mouse model was used to evaluate HMFS effects on metabolic parameters, liver histology, and lipid composition. Untargeted lipidomics identified candidate bioactive lipids. qPCR and Western blot were performed to assess hepatic gene and protein expression involved in lipid metabolism and signaling. Steatotic hepatocyte assays examined LPC 18:2 induced GPR119–AMPK activation. Molecular docking and molecular dynamics simulations were conducted to characterize LPC 18:2–GPR119 binding interactions.
Results
HMFS significantly reduced weight gain, hepatic triacylglycerols, and serum dyslipidemia, and improved liver enzyme profiles. Lipidomics revealed a marked elevation of LPC 18:2 alongside broad triacylglycerol reduction. HMFS upregulated enzymes involved in triacylglycerol hydrolysis and phospholipid remodeling, restoring hepatic GPR119–AMPK activation and promoting fatty acid oxidation over lipogenesis. Spearman correlation analysis revealed that LPC 18:2 levels were inversely correlated with obesity markers and positively correlated with GPR119–AMPK signaling. In vitro, LPC 18:2 replicated these effects in hepatocytes, reducing steatosis and enhancing AMPK phosphorylation. Computational analyses demonstrated stable LPC 18:2–GPR119 binding with favorable interaction energies.
Conclusion
HMFS alleviates diet-induced metabolic impairments in mice by enriching LPC 18:2, which activates GPR119–AMPK signaling to promote hepatic lipid catabolism. These findings provide mechanistic evidence supporting structured lipids as potential nutritional interventions for obesity-related liver disease.
{"title":"Human milk fat substitutes improve obesity-related NAFLD by enriching LPC 18:2 to activate hepatic GPR119–AMPK signaling","authors":"Yangzheng He, Jing Li, Zhigang Wen, Yong Sun, Liufeng Zheng, Hongyan Li, Zeyuan Deng","doi":"10.1016/j.jare.2026.01.083","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.083","url":null,"abstract":"<h3>Introduction</h3>Obesity-associated non-alcoholic fatty liver disease (NAFLD) remains a global health burden with limited treatment options. Human milk fat substitutes (HMFS), designed to mimic the triacylglycerol structure of breast milk, have shown potential metabolic benefits. However, the mechanisms underlying their effects on hepatic lipid metabolism remain unclear.<h3>Objectives</h3>This study aims to evaluate the therapeutic effects of HMFS on established high fat diet-induced metabolic dysfunction and to delineate the lipid-mediated pathways involved.<h3>Methods</h3>A high-fat diet–induced obese mouse model was used to evaluate HMFS effects on metabolic parameters, liver histology, and lipid composition. Untargeted lipidomics identified candidate bioactive lipids. qPCR and Western blot were performed to assess hepatic gene and protein expression involved in lipid metabolism and signaling. Steatotic hepatocyte assays examined LPC 18:2 induced GPR119–AMPK activation. Molecular docking and molecular dynamics simulations were conducted to characterize LPC 18:2–GPR119 binding interactions.<h3>Results</h3>HMFS significantly reduced weight gain, hepatic triacylglycerols, and serum dyslipidemia, and improved liver enzyme profiles. Lipidomics revealed a marked elevation of LPC 18:2 alongside broad triacylglycerol reduction. HMFS upregulated enzymes involved in triacylglycerol hydrolysis and phospholipid remodeling, restoring hepatic GPR119–AMPK activation and promoting fatty acid oxidation over lipogenesis. Spearman correlation analysis revealed that LPC 18:2 levels were inversely correlated with obesity markers and positively correlated with GPR119–AMPK signaling. <em>In vitro</em>, LPC 18:2 replicated these effects in hepatocytes, reducing steatosis and enhancing AMPK phosphorylation. Computational analyses demonstrated stable LPC 18:2–GPR119 binding with favorable interaction energies.<h3>Conclusion</h3>HMFS alleviates diet-induced metabolic impairments in mice by enriching LPC 18:2, which activates GPR119–AMPK signaling to promote hepatic lipid catabolism. These findings provide mechanistic evidence supporting structured lipids as potential nutritional interventions for obesity-related liver disease.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"58 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098418","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}
Pub Date : 2026-02-02DOI: 10.1016/j.jare.2026.01.080
Jiangwei Xia, Jiajian Li, Siqi Chen, Tianpeng Chang, Yu Qian, Ou Wu, Yang Wu, Yinan Zhao, Junwei Hao, Lianmei Zhong
Introduction
Numerous studies have identified a close association between visceral adipose tissue mass (VAT) and neuropsychiatric disorders (NPDs). Both VAT and NPDs exhibit high heritability, yet their shared genetic architecture remains unclear.
Objectives
We sought to delineate genetic correlations, locus-level pleiotropy, causal effects, tissue/pathway context, and therapeutic hypotheses linking VAT with ten neuropsychiatric traits (nine NPDs plus cognitive function) using large-scale GWASs.
Methods
We conducted genetic correlation, polygenic overlap, colocalization, transcriptome-wide association (TWAS), bidirectional two-sample Mendelian randomization (MR), and pathway-tissue-phenotype-drug enrichment analyses.
Results
We uncovered significant genetic correlations and causal relationships between VAT and NPDs, with a notable bidirectional association pattern. Pleiotropy analysis identified 681 shared independent genomic risk loci, 74 of which are novel, and 19 are causal variants. These pleiotropic loci are predominantly expressed in hypothalamic and related brain regions, influencing lipid metabolism, neurodevelopment, neurotransmitter regulation, and synaptic plasticity via the HPA axis. TWAS analysis prioritized NUCKS1, MED27, LMF1, and YWHAB as novel candidate causal genes. Drug enrichment analysis highlighted 5-HT1A-targeting agents (e.g., vortioxetine) and calcium channel blockers (e.g., CACNA1C) as potential therapies for comorbid NPDs and obesity.
Conclusion
These findings support a shared genetic framework for brain-adipose crosstalk centered on hypothalamic-synaptic mechanisms and highlight potential therapeutic targets for comorbid management.
{"title":"Neural – adipose crosstalk: Shared genetic architecture of visceral fat and neuropsychiatric disorders","authors":"Jiangwei Xia, Jiajian Li, Siqi Chen, Tianpeng Chang, Yu Qian, Ou Wu, Yang Wu, Yinan Zhao, Junwei Hao, Lianmei Zhong","doi":"10.1016/j.jare.2026.01.080","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.080","url":null,"abstract":"<h3>Introduction</h3>Numerous studies have identified a close association between visceral adipose tissue mass (VAT) and neuropsychiatric disorders (NPDs). Both VAT and NPDs exhibit high heritability, yet their shared genetic architecture remains unclear.<h3>Objectives</h3>We sought to delineate genetic correlations, locus-level pleiotropy, causal effects, tissue/pathway context, and therapeutic hypotheses linking VAT with ten neuropsychiatric traits (nine NPDs plus cognitive function) using large-scale GWASs.<h3>Methods</h3>We conducted genetic correlation, polygenic overlap, colocalization, transcriptome-wide association (TWAS), bidirectional two-sample Mendelian randomization (MR), and pathway-tissue-phenotype-drug enrichment analyses.<h3>Results</h3>We uncovered significant genetic correlations and causal relationships between VAT and NPDs, with a notable bidirectional association pattern. Pleiotropy analysis identified 681 shared independent genomic risk loci, 74 of which are novel, and 19 are causal variants. These pleiotropic loci are predominantly expressed in hypothalamic and related brain regions, influencing lipid metabolism, neurodevelopment, neurotransmitter regulation, and synaptic plasticity via the HPA axis. TWAS analysis prioritized <em>NUCKS1, MED27, LMF1,</em> and <em>YWHAB</em> as novel candidate causal genes. Drug enrichment analysis highlighted 5-HT1A-targeting agents (e.g., vortioxetine) and calcium channel blockers (e.g., CACNA1C) as potential therapies for comorbid NPDs and obesity.<h3>Conclusion</h3>These findings support a shared genetic framework for brain-adipose crosstalk centered on hypothalamic-synaptic mechanisms and highlight potential therapeutic targets for comorbid management.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098395","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}
Pub Date : 2026-02-01DOI: 10.1016/j.jare.2026.01.075
Lin Chen, Haibo Li, Qingtain Zhu, Xingmeng Xu, Xinyi Liu, Xiaowu Dong, Chenchen Yuan, Weiwei Chen, Weiming Xiao, Zifan Ding, Keyan Wu, Bo Tu, Wei Li, Xiaoyu Zhu, Weijuan Gong, Guotao Lu, Dan Ji
Introduction
The necroptosis regulator PGAM5 drives a pathological cycle of mitochondrial dysfunction and necroptotic signaling, contributing to multi-organ injury and representing a potential therapeutic target. Despite its clinical relevance, few PGAM5-specific small-molecule inhibitors have been developed.
Objectives
We aimed to identify a safe and effective natural small-molecule inhibitor targeting PGAM5 as a novel therapeutic strategy.
Methods
Global PGAM5 knockout mice and pancreas-specific PGAM5 knockdown mice were used to clarify the regulatory role of PGAM5 in pancreatic injury in acute pancreatitis (AP). Subsequently, high-throughput screening of candidate compounds targeting PGAM5 was conducted based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Combined with molecular docking, in vitro binding experiments, and functional verification experiments, Plantainoside D (PD) was finally identified as a natural small-molecule inhibitor targeting PGAM5. Finally, the protective effect of PD was evaluated using preclinical models of various organ injuries.
Results
We identify PGAM5 as a critical mediator of pancreatic acinar cell (PAC) necrosis in AP. Genetic suppression of PGAM5 significantly mitigates PAC necrosis in both in vitro and in vivo AP models. Through high-throughput virtual screening of the TCMSP natural-product database, we identified PD, a phenylethanoid glycoside, as the first reported PGAM5-specific small-molecule inhibitor. By binding PGAM5, PD inhibits its phosphatase activity and prevents oligomerization, thereby restoring mitochondrial homeostasis and blocking necroptosis. Importantly, systemic PD administration demonstrated broad protective efficacy in multiple organ-injury models—including autoimmune hepatitis, acute kidney injury, myocardial ischemia − reperfusion, and lung fibrosis − as well as local efficacy in a pathological high intraocular pressure(ph-IOP) − induced retinal ganglion cell (RGC) injury model.
Conclusion
These findings establish PGAM5 as a druggable target in organ injury and identify PD as a natural compound with favorable safety and strong translational potential, providing a foundation for necroptosis-targeted therapeutic development.
{"title":"Screening and identification of a novel PGAM5-specific inhibitor for attenuating multi-organ injury","authors":"Lin Chen, Haibo Li, Qingtain Zhu, Xingmeng Xu, Xinyi Liu, Xiaowu Dong, Chenchen Yuan, Weiwei Chen, Weiming Xiao, Zifan Ding, Keyan Wu, Bo Tu, Wei Li, Xiaoyu Zhu, Weijuan Gong, Guotao Lu, Dan Ji","doi":"10.1016/j.jare.2026.01.075","DOIUrl":"https://doi.org/10.1016/j.jare.2026.01.075","url":null,"abstract":"<h3>Introduction</h3>The necroptosis regulator PGAM5 drives a pathological cycle of mitochondrial dysfunction and necroptotic signaling, contributing to multi-organ injury and representing a potential therapeutic target. Despite its clinical relevance, few PGAM5-specific small-molecule inhibitors have been developed.<h3>Objectives</h3>We aimed to identify a safe and effective natural small-molecule inhibitor targeting PGAM5 as a novel therapeutic strategy.<h3>Methods</h3>Global PGAM5 knockout mice and pancreas-specific PGAM5 knockdown mice were used to clarify the regulatory role of PGAM5 in pancreatic injury in acute pancreatitis (AP). Subsequently, high-throughput screening of candidate compounds targeting PGAM5 was conducted based on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Combined with molecular docking, <em>in vitro</em> binding experiments, and functional verification experiments, Plantainoside D (PD) was finally identified as a natural small-molecule inhibitor targeting PGAM5. Finally, the protective effect of PD was evaluated using preclinical models of various organ injuries.<h3>Results</h3>We identify PGAM5 as a critical mediator of pancreatic acinar cell (PAC) necrosis in AP. Genetic suppression of PGAM5 significantly mitigates PAC necrosis in both <em>in vitro</em> and <em>in vivo</em> AP models. Through high-throughput virtual screening of the TCMSP natural-product database, we identified PD, a phenylethanoid glycoside, as the first reported PGAM5-specific small-molecule inhibitor. By binding PGAM5, PD inhibits its phosphatase activity and prevents oligomerization, thereby restoring mitochondrial homeostasis and blocking necroptosis. Importantly, systemic PD administration demonstrated broad protective efficacy in multiple organ-injury models—including autoimmune hepatitis, acute kidney injury, myocardial ischemia − reperfusion, and lung fibrosis − as well as local efficacy in a pathological high intraocular pressure(ph-IOP) − induced retinal ganglion cell (RGC) injury model.<h3>Conclusion</h3>These findings establish PGAM5 as a druggable target in organ injury and identify PD as a natural compound with favorable safety and strong translational potential, providing a foundation for necroptosis-targeted therapeutic development.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"253 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146101851","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}
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