Intervertebral disc degeneration (IVDD), a major cause of low back pain, is primarily characterized by compromised regeneration ability of nucleus pulposus-derived stem cells (NPSCs) owing to their senescence. The role of NPSCs as major regenerative cells in IVDD is garnering attention. However, the drivers and mechanisms of NPSCs reactivation and regeneration are poorly understood, limiting the development of targeted therapies. The fibroblast growth factor (FGF) family has shown increasing promise in tissue regeneration; however, the key factors involved in IVDD remain unclear.
Objectives
To elucidate the regenerative driver of NPSCs and the underlying anti-senescence mechanism to provide a potential therapeutic strategy.
Methods
Single cell RNA sequencing (scRNA-seq) and bulk RNA sequencing were performed to identify the key NPSCs clusters and regenerative drivers in IVDD. Clinical IVDD samples were collected to determine the alterations in the NPSCs subset proportion and the expression of regeneration factors. Further, NPSCs senescence and in vivo models were used to investigate the specific mechanisms and therapeutic effects.
Results
Thy-1 membrane glycoprotein (THY1)+ NPSCs, which are depleted in IVDD, were the key cells involved in intervertebral disc degeneration based on scRNA-seq. THY1+ NPSCs exhibited stemness and regeneration potential. The RNA-seq analysis of senescent THY1+ NPSCs indicated fibroblast growth factor 10 (FGF10) as a pivotal rejuvenation factor. Multiplex fluorescence staining demonstrated diminished FGF10 expression in IVDD. FGF10 mitigated THY1+ NPSCs senescence by interacting with fibroblast growth factor receptor 1 (FGFR1). The FGF10-FGFR1 axis inhibited CREB phosphorylation and further alleviated ARG2-DRP1-related mitochondrial fission, reversing THY1+ NPSC senescence. Inhibition of CREB and downregulation of ARG2 regulate cellular senescence via modulation of mitochondrial fission. The transplantation of FGF10-overexpression NPSCs prominently alleviated nucleus pulposus degeneration and demonstrated regeneration potential in vivo.
Conclusion
Our findings elucidate the pivotal roles of THY1+ NPSCs and FGF10 in intervertebral disc regeneration and NPSCs activation, respectively, contributing to the development of regenerative therapeutic strategies for IVDD
{"title":"Rejuvenation of THY1+ nucleus pulposus-derived stem cells promotes intervertebral disc regeneration through FGF10-FGFR1-CREB pathway and mitochondrial fission","authors":"Haoxin Zhai, Zexin Wang, Shaoyi Wang, Zhicheng Liu, Dawang Zhao, Yiming Zhang, Kaiwen Liu, Xiangzhen Kong, Qunbo Meng, Hanwen Gu, Lin Chen, Yuanqiang Zhang, Lei Cheng","doi":"10.1016/j.jare.2026.03.008","DOIUrl":"https://doi.org/10.1016/j.jare.2026.03.008","url":null,"abstract":"<h3>Introduction</h3>Intervertebral disc degeneration (IVDD), a major cause of low back pain, is primarily characterized by compromised regeneration ability of nucleus pulposus-derived stem cells (NPSCs) owing to their senescence. The role of NPSCs as major regenerative cells in IVDD is garnering attention. However, the drivers and mechanisms of NPSCs reactivation and regeneration are poorly understood, limiting the development of targeted therapies. The fibroblast growth factor (FGF) family has shown increasing promise in tissue regeneration; however, the key factors involved in IVDD remain unclear.<h3>Objectives</h3>To elucidate the regenerative driver of NPSCs and the underlying anti-senescence mechanism to provide a potential therapeutic strategy.<h3>Methods</h3>Single cell RNA sequencing (scRNA-seq) and bulk RNA sequencing were performed to identify the key NPSCs clusters and regenerative drivers in IVDD. Clinical IVDD samples were collected to determine the alterations in the NPSCs subset proportion and the expression of regeneration factors. Further, NPSCs senescence and in vivo models were used to investigate the specific mechanisms and therapeutic effects.<h3>Results</h3>Thy-1 membrane glycoprotein (THY1)<sup>+</sup> NPSCs, which are depleted in IVDD, were the key cells involved in intervertebral disc degeneration based on scRNA-seq. THY1<sup>+</sup> NPSCs exhibited stemness and regeneration potential. The RNA-seq analysis of senescent THY1<sup>+</sup> NPSCs indicated fibroblast growth factor 10 (FGF10) as a pivotal rejuvenation factor. Multiplex fluorescence staining demonstrated diminished FGF10 expression in IVDD. FGF10 mitigated THY1<sup>+</sup> NPSCs senescence by interacting with fibroblast growth factor receptor 1 (FGFR1). The FGF10-FGFR1 axis inhibited CREB phosphorylation and further alleviated ARG2-DRP1-related mitochondrial fission, reversing THY1<sup>+</sup> NPSC senescence. Inhibition of CREB and downregulation of ARG2 regulate cellular senescence via modulation of mitochondrial fission. The transplantation of FGF10-overexpression NPSCs prominently alleviated nucleus pulposus degeneration and demonstrated regeneration potential <em>in vivo</em>.<h3>Conclusion</h3>Our findings elucidate the pivotal roles of THY1<sup>+</sup> NPSCs and FGF10 in intervertebral disc regeneration and NPSCs activation, respectively, contributing to the development of regenerative therapeutic strategies for IVDD","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"15 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147384032","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}
Microglial activation represents a central pathological hallmark of Parkinson’s disease (PD), characterized by a distinct metabolic reprogramming from oxidative phosphorylation toward glycolysis during pro-inflammatory activation. This metabolic shift drives lactate accumulation and subsequent protein lactylation, which has been increasingly implicated in PD development. However, the molecular mechanisms through which protein lactylation exerts its pathological effects remain largely unknown.
{"title":"Microglia Dld-K127 lactylation promotes Parkinson’s disease via regulating the metabolism of lactate-pyruvate transformation","authors":"Guoqing Wang, Guichun Gong, Xinxing Yang, Yanran Qian, Yujia Zhao, Daidi Li, Mei Liu, Zucai Xu, Feng Zhang","doi":"10.1016/j.jare.2026.03.016","DOIUrl":"https://doi.org/10.1016/j.jare.2026.03.016","url":null,"abstract":"Microglial activation represents a central pathological hallmark of Parkinson’s disease (PD), characterized by a distinct metabolic reprogramming from oxidative phosphorylation toward glycolysis during pro-inflammatory activation. This metabolic shift drives lactate accumulation and subsequent protein lactylation, which has been increasingly implicated in PD development. However, the molecular mechanisms through which protein lactylation exerts its pathological effects remain largely unknown.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"14 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393132","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}
The continuous circulation of H7N9 avian influenza viruses (AIVs) in poultry poses a significant public health threat. T cell-mediated immunity favors enhanced and broad protection against viruses. However, it remains challenging to exploit avian T-cell immunity for improving vaccine efficacy. Here, we showed that vaccine-induced hemagglutinin (HA)-specific T-cell responses promoted broad protection against heterologous H7N9 in poultry. Four conserved epitopes of H7N9 HA recognized by chicken T cells were identified, including two CD4 T-cell epitopes (P12, P15), one CD8 T-cell epitope (P4), and one dual-recognized epitope peptide (P10). These peptides were pooled (PP) and incorporated into an H7N9 whole inactivated virus (WIV) vaccine via a DDA/TDB nanoparticle platform (H7N9 WIV + PP) for better delivery and presentation of diverse T-cell epitopes. The results showed that H7N9 WIV + PP vaccination elicited more robust humoral and cellular immune responses than the H7N9 WIV alone and conferred broad protection against antigenically divergent H7N9 virus challenge. Mechanistically, pooled T-cell epitope supplementation enhanced the elicitation of HA peptide-specific T-cell responses, which in turn boosted HA-specific antibodies via peptide-specific CD4<sup>+</sup> T-cell help while concurrently mobilizing protective CD4<sup>+</sup> and CD8<sup>+</sup> T-cell immunity and effector molecules. Our study offers a novel strategy for developing broad-spectrum poultry vaccines against evolving AIV strains. Introduction: The persistent circulation of H7N9 avian influenza viruses (AIVs) in poultry continues to threaten public health. While T cell-mediated immunity is known to enhance and promote cross-protective antiviral responses, exploiting avian T-cell immunity for improved vaccine efficacy remains challenging. Hemagglutinin (HA)-specific T-cell responses may serve as a key mechanism to broaden protection against antigenically diverse H7N9 strains. Objectives: This study aimed to determine whether HA-specific T-cell responses can enhance heterologous protection against H7N9 in poultry and whether T-cell epitope-supplemented vaccines can improve both humoral and cellular immunity. Methods: Conserved HA epitopes recognized by chicken T cells were identified using immunological assays, resulting in two CD4 epitopes (P12, P15), one CD8 epitope (P4), and one dual-recognized epitope (P10). These peptides were pooled (PP) and incorporated into an H7N9 whole inactivated virus (WIV) vaccine formulated with a DDA/TDB nanoparticle adjuvant (H7N9 WIV + PP). Immune responses and protection were assessed following homologous and heterologous H7N9 virus challenge. Results: The H7N9 WIV + PP vaccine elicited stronger humoral and cellular immune responses compared with WIV alone. Birds receiving H7N9 WIV + PP displayed significantly improved protection against antigenically divergent H7N9 challenge. Mechanistically, pooled epitope supplementation enhanced HA peptide-spe
{"title":"T-cell epitope supplementation enhanced cross-protection against H7N9 AIV in chickens via upregulated HA epitope-specific T cell and CD4 T cell-mediated help","authors":"Xiaoli Hao, Xinjie Yuan, Jiongjiong Wang, Zhonglong Song, Xiaona Li, Chuang Meng, Yi Yang, Tao Qin, Jiao Hu, Min Gu, Shunlin Hu, Xiaoquan Wang, Xiaowen Liu, Daxin Peng, Xiufan Liu, Shaobin Shang","doi":"10.1016/j.jare.2026.03.012","DOIUrl":"https://doi.org/10.1016/j.jare.2026.03.012","url":null,"abstract":"The continuous circulation of H7N9 avian influenza viruses (AIVs) in poultry poses a significant public health threat. T cell-mediated immunity favors enhanced and broad protection against viruses. However, it remains challenging to exploit avian T-cell immunity for improving vaccine efficacy. Here, we showed that vaccine-induced hemagglutinin (HA)-specific T-cell responses promoted broad protection against heterologous H7N9 in poultry. Four conserved epitopes of H7N9 HA recognized by chicken T cells were identified, including two CD4 T-cell epitopes (P12, P15), one CD8 T-cell epitope (P4), and one dual-recognized epitope peptide (P10). These peptides were pooled (PP) and incorporated into an H7N9 whole inactivated virus (WIV) vaccine via a DDA/TDB nanoparticle platform (H7N9 WIV + PP) for better delivery and presentation of diverse T-cell epitopes. The results showed that H7N9 WIV + PP vaccination elicited more robust humoral and cellular immune responses than the H7N9 WIV alone and conferred broad protection against antigenically divergent H7N9 virus challenge. Mechanistically, pooled T-cell epitope supplementation enhanced the elicitation of HA peptide-specific T-cell responses, which in turn boosted HA-specific antibodies via peptide-specific CD4<sup>+</sup> T-cell help while concurrently mobilizing protective CD4<sup>+</sup> and CD8<sup>+</sup> T-cell immunity and effector molecules. Our study offers a novel strategy for developing broad-spectrum poultry vaccines against evolving AIV strains. Introduction: The persistent circulation of H7N9 avian influenza viruses (AIVs) in poultry continues to threaten public health. While T cell-mediated immunity is known to enhance and promote cross-protective antiviral responses, exploiting avian T-cell immunity for improved vaccine efficacy remains challenging. Hemagglutinin (HA)-specific T-cell responses may serve as a key mechanism to broaden protection against antigenically diverse H7N9 strains. Objectives: This study aimed to determine whether HA-specific T-cell responses can enhance heterologous protection against H7N9 in poultry and whether T-cell epitope-supplemented vaccines can improve both humoral and cellular immunity. Methods: Conserved HA epitopes recognized by chicken T cells were identified using immunological assays, resulting in two CD4 epitopes (P12, P15), one CD8 epitope (P4), and one dual-recognized epitope (P10). These peptides were pooled (PP) and incorporated into an H7N9 whole inactivated virus (WIV) vaccine formulated with a DDA/TDB nanoparticle adjuvant (H7N9 WIV + PP). Immune responses and protection were assessed following homologous and heterologous H7N9 virus challenge. Results: The H7N9 WIV + PP vaccine elicited stronger humoral and cellular immune responses compared with WIV alone. Birds receiving H7N9 WIV + PP displayed significantly improved protection against antigenically divergent H7N9 challenge. Mechanistically, pooled epitope supplementation enhanced HA peptide-spe","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"32 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147384033","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 : 2026-03-09DOI: 10.1016/j.jare.2026.03.001
Fan Liu, Xueli Sun, Ou Sheng, Tongxin Dou, Jiangshan Jian, Qiaosong Yang, Chunhua Hu, Guiming Deng, Weidi He, Huijun Gao, Tao Dong, Chunyu Li, Yaoyao Li, Cancan Liu, Ganjun Yi, Fangcheng Bi
Introduction
Fruit ripening is a genetically predetermined developmental process that is governed by a complex multilevel regulatory network requiring the orchestration of spatiotemporal expression of many genes and proteins. The GAI-RGA- and −SCRs (GRASs) are plant-exclusive transcription factors, which play pivotal regulatory roles in modulating growth, developmental processes, and environmental stress adaptation. However, the functional characterization and molecular mechanisms of GRASs in fruit ripening regulation remain poorly understood.
Objectives
This research was designed to elucidate the regulatory mechanism of MaSCL8 controlling banana ripening processes.
Methods
Yeast one-hybrid assay, dual luciferase reporter assay, and electrophoretic mobility shift assay were used to look for downstream target genes and upstream regulators of MaSCL8. We further performed luciferase complementation imaging and yeast two-hybrid assays to screen and verify MaSCL8-interacting proteins. Finally, the function of MaSCL8 was analyzed by stable overexpression in tomato and transient overexpression in banana.
Results
This study demonstrated that a GRAS gene, MaSCL8, positively regulates banana fruit ripening. MaSCL8 functioned as a nuclear-localized transcriptional activator and could physically interact with the promoter regions of MaAMY3, MaBAM9b, MaEXPA15, MaEXP21, MaPL3, and MaACO1, consequently enhancing their transcription. MaSCL8 overexpression in tomato and banana accelerated ripening processes by inducing the transcription of ethylene biosynthesis and softening related genes. Interestingly, MaBEL1 formed a heterodimer with MaSCL8, enhancing the MaSCL8-activated transcription of its target genes. In addition, we found that MaEIL9-MabZIP5 transcriptional cascade act upstream of MaSCL8 and activate the expression of MaSCL8 by physically interacting with its promoter.
Conclusion
Our findings indicate the MaEIL9–MaZIP5–MaSCL8 module cooperates with MaBEL1, contributing to banana ripening by improving ethylene production, starch degradation and cell wall disassembly. These results advance the fundamental understanding of GRAS-mediated ripening mechanisms.
{"title":"The MaEIL9-MaZIP5–MaSCL8 module integrates MaBEL1 and synergistically modulates banana fruit ripening","authors":"Fan Liu, Xueli Sun, Ou Sheng, Tongxin Dou, Jiangshan Jian, Qiaosong Yang, Chunhua Hu, Guiming Deng, Weidi He, Huijun Gao, Tao Dong, Chunyu Li, Yaoyao Li, Cancan Liu, Ganjun Yi, Fangcheng Bi","doi":"10.1016/j.jare.2026.03.001","DOIUrl":"https://doi.org/10.1016/j.jare.2026.03.001","url":null,"abstract":"<h3>Introduction</h3>Fruit ripening is a genetically predetermined developmental process that is governed by a complex multilevel regulatory network requiring the orchestration of spatiotemporal expression of many genes and proteins. The GAI-RGA- and −SCRs (GRASs) are plant-exclusive transcription factors, which play pivotal regulatory roles in modulating growth, developmental processes, and environmental stress adaptation. However, the functional characterization and molecular mechanisms of GRASs in fruit ripening regulation remain poorly understood.<h3>Objectives</h3>This research was designed to elucidate the regulatory mechanism of MaSCL8 controlling banana ripening processes.<h3>Methods</h3>Yeast one-hybrid assay, dual luciferase reporter assay, and electrophoretic mobility shift assay were used to look for downstream target genes and upstream regulators of <em>MaSCL8</em>. We further performed luciferase complementation imaging and yeast two-hybrid assays to screen and verify MaSCL8-interacting proteins. Finally, the function of <em>MaSCL8</em> was analyzed by stable overexpression in tomato and transient overexpression in banana.<h3>Results</h3>This study demonstrated that a <em>GRAS</em> gene, <em>MaSCL8</em>, positively regulates banana fruit ripening. MaSCL8 functioned as a nuclear-localized transcriptional activator and could physically interact with the promoter regions of <em>MaAMY3</em>, <em>MaBAM9b</em>, <em>MaEXPA15</em>, <em>MaEXP21</em>, <em>MaPL3</em>, and <em>MaACO1,</em> consequently enhancing their transcription. <em>MaSCL8</em> overexpression in tomato and banana accelerated ripening processes by inducing the transcription of ethylene biosynthesis and softening related genes. Interestingly, MaBEL1 formed a heterodimer with MaSCL8, enhancing the MaSCL8-activated transcription of its target genes. In addition, we found that MaEIL9-MabZIP5 transcriptional cascade act upstream of <em>MaSCL8</em> and activate the expression of <em>MaSCL8</em> by physically interacting with its promoter.<h3>Conclusion</h3>Our findings indicate the MaEIL9–MaZIP5–MaSCL8 module cooperates with MaBEL1, contributing to banana ripening by improving ethylene production, starch degradation and cell wall disassembly. These results advance the fundamental understanding of GRAS-mediated ripening mechanisms.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147384034","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 : 2026-03-09DOI: 10.1016/j.jare.2026.03.011
Yucheng Xiang, Lie Zhang, Jing Ye, Yu Chen, Qiao Ren, Bingyin Su, Xiaohong Xu, Quan Zhang
Introduction
Tumor fibrosis promotes immunosuppression by creating physical barrier that limits immune cell infiltration, posing challenges for immunotherapy. Therefore, it is essential to design a reasoned therapeutic strategy to surmount the tumor immune privilege by activating antitumor immunity and simultaneously destroying the physiological barriers of tumor microenvironment.
Objectives
Aim to develop a fibroblast-activated protein-α (FAP-α) responsive nanoparticle delivery system, (α-GC/NAV)-CPC, which encapsulates navitoclax (NAV) and alpha-galactosylceramide (α-GC). Upon reaching tumor site, the nanoparticles would be disassembled by FAP-α in tumor. The released α-GC activates natural killer T (NKT) and in parallel, the released NAV eliminates cancer associated fibroblasts (CAFs), ultimately breaking down physical barrier and realizing potent anti-tumor activity.
Methods
To maintain the self-assembly ability and FAP-α responsiveness, the designed amphiphilic block polymers consist of PEG chain as the hydrophilic domain, terminal cholesterol as the hydrophobic domain and FAP-α degradable amino acid residue sequence linkage (Ala-Thr-Gly-Pro-Ala). At the tissue level, the tumor specific fibrosis barrier destroying ability of (α-GC/NAV)-CPC was investigated. Subsequently, the NAV and α-GC were co-encapsulated into nanoparticles. The tumor accumulation, tumoricidal and anti-metastasis efficacy were validated in triple negative breast cancer-bearing models.
Results
This strategy can efficiently break down the cancer associated fibroblast based physical barrier. Encapsulated NAV can significantly decrease tumor interstitial fluid pressure (IFP), indicating as 4.9-fold lower than saline control group. Consequently, enhanced tumor infiltration and penetration of immune cells were observed. By quantitative flow-cytometry analysis, the abundances of NKT and T cells in tumors after (NAV/α-GC)-CPC treatment increased over 5 times and 4 times respectively, compared with saline treatment. Encouragingly, in in vivo models, (α-GC/NAV)-CPC treatment even led to 66.7% of mice achieving tumor eradication without recurrence. In further pulmonary metastasis challenge, mice treated with (α-GC/NAV)-CPC rarely displayed lung metastatic nodules.
{"title":"Co-delivery nanoparticle targeting CAF for simultaneous activating T cell plus NKT cell attack in solid tumor","authors":"Yucheng Xiang, Lie Zhang, Jing Ye, Yu Chen, Qiao Ren, Bingyin Su, Xiaohong Xu, Quan Zhang","doi":"10.1016/j.jare.2026.03.011","DOIUrl":"https://doi.org/10.1016/j.jare.2026.03.011","url":null,"abstract":"<h3>Introduction</h3>Tumor fibrosis promotes immunosuppression by creating physical barrier that limits immune cell infiltration, posing challenges for immunotherapy. Therefore, it is essential to design a reasoned therapeutic strategy to surmount the tumor immune privilege by activating antitumor immunity and simultaneously destroying the physiological barriers of tumor microenvironment.<h3>Objectives</h3>Aim to develop a fibroblast-activated protein-α (FAP-α) responsive nanoparticle delivery system, (α-GC/NAV)-CPC, which encapsulates navitoclax (NAV) and alpha-galactosylceramide (α-GC). Upon reaching tumor site, the nanoparticles would be disassembled by FAP-α in tumor. The released α-GC activates natural killer T (NKT) and in parallel, the released NAV eliminates cancer associated fibroblasts (CAFs), ultimately breaking down physical barrier and realizing potent anti-tumor activity.<h3>Methods</h3>To maintain the self-assembly ability and FAP-α responsiveness, the designed amphiphilic block polymers consist of PEG chain as the hydrophilic domain, terminal cholesterol as the hydrophobic domain and FAP-α degradable amino acid residue sequence linkage (Ala-Thr-Gly-Pro-Ala). At the tissue level, the tumor specific fibrosis barrier destroying ability of (α-GC/NAV)-CPC was investigated. Subsequently, the NAV and α-GC were co-encapsulated into nanoparticles. The tumor accumulation, tumoricidal and anti-metastasis efficacy were validated in triple negative breast cancer-bearing models.<h3>Results</h3>This strategy can efficiently break down the cancer associated fibroblast based physical barrier. Encapsulated NAV can significantly decrease tumor interstitial fluid pressure (IFP), indicating as 4.9-fold lower than saline control group. Consequently, enhanced tumor infiltration and penetration of immune cells were observed. By quantitative flow-cytometry analysis, the abundances of NKT and T cells in tumors after (NAV/α-GC)-CPC treatment increased over 5 times and 4 times respectively, compared with saline treatment. Encouragingly, in <em>in vivo</em> models, (α-GC/NAV)-CPC treatment even led to 66.7% of mice achieving tumor eradication without recurrence. In further pulmonary metastasis challenge, mice treated with (α-GC/NAV)-CPC rarely displayed lung metastatic nodules.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"226 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380672","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}
Iron metabolism imbalance is closely associated with gestational diabetes mellitus (GDM), but the underlying mechanisms of its contribution to placental endothelial dysfunction and effective interventions remain unclear.
Methods
Pregnant mice and sow models with impaired glucose tolerance, along with placental samples from women with GDM, were used to investigate the effects of abnormal glucose metabolism on placental iron homeostasis and angiogenesis. In vitro, endothelial cells and mouse allantois were treated with high glucose and palmitic acid to mimic metabolic-induced vascular injury. The potential therapeutic role of docosahexaenoic acid (DHA) in reversing these placental impairments was further evaluated.
Results
We show that a ferroptosis-prone state in the placenta under glucose intolerance is linked to impaired angiogenesis and that DHA supplementation can alleviate endothelial ferroptosis and vascular dysfunction by down-regulating placental hepcidin (HAMP) expression. Mechanistically, DHA reverses the reduction in PARP1 binding to the promoter and the overexpression of SREBF2 induced by glucose intolerance, and restores the inhibitory effect of PARP1 on histone acetylation at the Hamp promoter, thereby reducing endothelial HAMP expression, promoting intracellular ferrous iron efflux and ultimately improving angiogenic capacity.
Conclusions
These findings reveal the critical role of iron dysregulation in placental endothelial impairment during GDM progression and highlight the therapeutic potential of DHA in restoring placental iron homeostasis and angiogenesis via placental HAMP regulation.
{"title":"DHA ameliorates GDM placental angiogenesis by regulating HAMP-mediated iron imbalance","authors":"Zihao Huang, Shijian Zhou, Zhijuan Cui, Jinfeng Li, Liudan Liu, Xuexun Feng, Hongxuan Ye, Kaidi Ma, Shuangbo Huang, Quanhang Xiang, Wei Shi, Jinping Deng, Chengquan Tan","doi":"10.1016/j.jare.2026.03.005","DOIUrl":"https://doi.org/10.1016/j.jare.2026.03.005","url":null,"abstract":"<h3>Introduction</h3>Iron metabolism imbalance is closely associated with gestational diabetes mellitus (GDM), but the underlying mechanisms of its contribution to placental endothelial dysfunction and effective interventions remain unclear.<h3>Methods</h3>Pregnant mice and sow models with impaired glucose tolerance, along with placental samples from women with GDM, were used to investigate the effects of abnormal glucose metabolism on placental iron homeostasis and angiogenesis. In vitro, endothelial cells and mouse allantois were treated with high glucose and palmitic acid to mimic metabolic-induced vascular injury. The potential therapeutic role of docosahexaenoic acid (DHA) in reversing these placental impairments was further evaluated.<h3>Results</h3>We show that a ferroptosis-prone state in the placenta under glucose intolerance is linked to impaired angiogenesis and that DHA supplementation can alleviate endothelial ferroptosis and vascular dysfunction by down-regulating placental hepcidin (HAMP) expression. Mechanistically, DHA reverses the reduction in PARP1 binding to the promoter and the overexpression of SREBF2 induced by glucose intolerance, and restores the inhibitory effect of PARP1 on histone acetylation at the <em>Hamp</em> promoter, thereby reducing endothelial HAMP expression, promoting intracellular ferrous iron efflux and ultimately improving angiogenic capacity.<h3>Conclusions</h3>These findings reveal the critical role of iron dysregulation in placental endothelial impairment during GDM progression and highlight the therapeutic potential of DHA in restoring placental iron homeostasis and angiogenesis via placental HAMP regulation.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"47 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380675","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 : 2026-03-09DOI: 10.1016/j.jare.2026.03.010
Xiaoqi Li, Tianyuan Zhao, Guoxin Li, Qing Zhong, Zhengwen An
The immune microenvironment in head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and dynamic system that plays a crucial role in tumor progression and therapeutic response. While T cell-mediated immunity has been extensively studied, B cells, an equally important component of the adaptive immune system, are gaining increasing attention for their diverse and sometimes contradictory roles within the HNSCC tumor microenvironment (TME). The plasticity of B cells contributes to both anti-tumor and pro-tumor immunity through different mechanisms, highlighting their dual regulatory capacity. Human papillomavirus (HPV) infection, a critical etiological factor and prognostic marker in HNSCC, significantly influences the composition, distribution and functional state of B cells in the TME. In this review, we systematically examine the phenotypic and functional differences in B cell populations in HPV+ versus HPV− HNSCC. We further discuss how HPV status shapes B cell behavior and propose that elucidating the signaling pathways and differentiation trajectories influenced by HPV could reveal critical mechanisms of B cell-mediated immunity. These insights hold potential for refining immunotherapeutic strategies and improving clinical outcomes for HNSCC patients.
{"title":"HPV-dependent divergence of B cell immunity in head and neck squamous cell carcinoma","authors":"Xiaoqi Li, Tianyuan Zhao, Guoxin Li, Qing Zhong, Zhengwen An","doi":"10.1016/j.jare.2026.03.010","DOIUrl":"https://doi.org/10.1016/j.jare.2026.03.010","url":null,"abstract":"The immune microenvironment in head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and dynamic system that plays a crucial role in tumor progression and therapeutic response. While T cell-mediated immunity has been extensively studied, B cells, an equally important component of the adaptive immune system, are gaining increasing attention for their diverse and sometimes contradictory roles within the HNSCC tumor microenvironment (TME). The plasticity of B cells contributes to both anti-tumor and pro-tumor immunity through different mechanisms, highlighting their dual regulatory capacity. Human papillomavirus (HPV) infection, a critical etiological factor and prognostic marker in HNSCC, significantly influences the composition, distribution and functional state of B cells in the TME. In this review, we systematically examine the phenotypic and functional differences in B cell populations in HPV<sup>+</sup> versus HPV<sup>−</sup> HNSCC. We further discuss how HPV status shapes B cell behavior and propose that elucidating the signaling pathways and differentiation trajectories influenced by HPV could reveal critical mechanisms of B cell-mediated immunity. These insights hold potential for refining immunotherapeutic strategies and improving clinical outcomes for HNSCC patients.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"44 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380674","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 : 2026-03-09DOI: 10.1016/j.jare.2026.03.004
Libing Xu, Liying Guo, Qunchao Su, Qianwen Shao, Yong Lu, Yanhong Nie, Yunpeng Yang, Qiang Sun
Introduction
Dietary intervention has emerged as a promising approach for improving metabolic health across species; however, its systemic effects in non-human primates (NHPs) remain insufficiently characterized.
Objectives
We sought to investigate the metabolic and physiological impacts of time-restricted intermittent fasting (IF) regimen that resulted in a net energy deficit in overweight female cynomolgus monkeys, both during the intervention and after dietary reversal, with particular focus on body weight, metabolic parameters, immune cell ratios, gut microbiota, and serum metabolomic profiles.
Methods
Overweight monkeys underwent 20-hour fasting/4-hour feeding IF protocol for 84 days, subsequently entering 42-day post-intervention phase where animals either continued IF (HW-IF-IF, n = 8) or resumed normal feeding (HW-IF-NF, n = 8). Normal-weight (Con-NF, n = 8) and high-weight control (HW-NF, n = 7) groups maintained standard feeding served as controls. We monitored body weight and measured serum triglycerides, insulin levels, and insulin resistance. Immune cell percentages were determined by flow cytometry. Gut microbiome was profiled via 16S rRNA sequencing. Serum metabolomic profiling was conducted using untargeted metabolomics.
Results
IF promoted significant reductions in body weight (day126, p = 0.0421), serum triglycerides (day126, p = 0.0108), insulin levels (day126, p = 0.0107), and insulin resistance (day126, p = 0.0004) in overweight monkeys. The insulin-lowering effects and enhanced insulin sensitivity were maintained even after reintroduction of normal feeding. By day 126, the sustained increase in lymphocyte-to-neutrophil ratio was exclusive to the continuous intermittent fasting group (HW-IF-IF), suggesting a potential immunomodulatory effect of prolonged fasting. Longitudinal gut microbiota analysis indicated that the gut microbiota structure underwent limited compositional changes. Nevertheless, time-dependent enrichments emerged in several genera, including Ruminococcus, Eubacterium_hallii_group, and Monoglobus. Serum metabolomics unveiled pronounced time-dependent alterations in circulating metabolites.
Conclusion
These findings elucidate physiological and metabolic adaptations to specified IF-refeeding regimen in cynomolgus monkeys and establish a framework for mechanistic studies of fasting-induced metabolic responses in non-human primates.
饮食干预已成为改善跨物种代谢健康的一种有前途的方法；然而，其对非人灵长类动物（NHPs）的系统性影响尚未充分表征。我们试图研究限时间歇性禁食（IF）方案在干预期间和饮食逆转后导致超重雌性食蟹猴净能量不足的代谢和生理影响，特别关注体重、代谢参数、免疫细胞比率、肠道微生物群和血清代谢组学特征。方法超重猴子进行为期84 天的20小时空腹/4小时摄食IF方案，随后进入42天的干预后阶段，动物继续进行IF （HW-IF-IF, n = 8）或恢复正常摄食（HW-IF-NF, n = 8）。正常体重组（Con-NF, n = 8）和高体重对照组（HW-NF, n = 7）维持标准喂养作为对照组。我们监测了体重，测量了血清甘油三酯、胰岛素水平和胰岛素抵抗。流式细胞术检测免疫细胞百分比。通过16S rRNA测序分析肠道微生物组。使用非靶向代谢组学进行血清代谢组学分析。结果tsif显著降低了超重猴子的体重（第126天，p = 0.0421）、血清甘油三酯（第126天，p = 0.0108）、胰岛素水平（第126天，p = 0.0107）和胰岛素抵抗（第126天，p = 0.0004）。即使在重新引入正常喂养后，胰岛素降低效果和胰岛素敏感性仍保持增强。到第126天，持续间歇性禁食组（HW-IF-IF）的淋巴细胞/中性粒细胞比率持续升高，提示长时间禁食可能具有免疫调节作用。纵向肠道菌群分析表明，肠道菌群结构发生了有限的组成变化。然而，在一些属中出现了时间依赖性的富集，包括Ruminococcus， Eubacterium_hallii_group和monglobus。血清代谢组学揭示了循环代谢物明显的时间依赖性改变。结论本研究结果阐明了食蟹猴对特定进食方式的生理和代谢适应，并为非人类灵长类动物禁食诱导代谢反应的机制研究奠定了基础。
{"title":"Dynamic impact of intermittent fasting and refeeding on metabolic health and microbiome-metabolome signatures in cynomolgus monkeys","authors":"Libing Xu, Liying Guo, Qunchao Su, Qianwen Shao, Yong Lu, Yanhong Nie, Yunpeng Yang, Qiang Sun","doi":"10.1016/j.jare.2026.03.004","DOIUrl":"https://doi.org/10.1016/j.jare.2026.03.004","url":null,"abstract":"<h3>Introduction</h3>Dietary intervention has emerged as a promising approach for improving metabolic health across species; however, its systemic effects in non-human primates (NHPs) remain insufficiently characterized.<h3>Objectives</h3>We sought to investigate the metabolic and physiological impacts of time-restricted intermittent fasting (IF) regimen that resulted in a net energy deficit in overweight female cynomolgus monkeys, both during the intervention and after dietary reversal, with particular focus on body weight, metabolic parameters, immune cell ratios, gut microbiota, and serum metabolomic profiles.<h3>Methods</h3>Overweight monkeys underwent 20-hour fasting/4-hour feeding IF protocol for 84 days, subsequently entering 42-day post-intervention phase where animals either continued IF (HW-IF-IF, n = 8) or resumed normal feeding (HW-IF-NF, n = 8). Normal-weight (Con-NF, n = 8) and high-weight control (HW-NF, n = 7) groups maintained standard feeding served as controls. We monitored body weight and measured serum triglycerides, insulin levels, and insulin resistance. Immune cell percentages were determined by flow cytometry. Gut microbiome was profiled via 16S rRNA sequencing. Serum metabolomic profiling was conducted using untargeted metabolomics.<h3>Results</h3>IF promoted significant reductions in body weight (day126, <em>p</em> = 0.0421), serum triglycerides (day126, <em>p</em> = 0.0108), insulin levels (day126, <em>p</em> = 0.0107), and insulin resistance (day126, <em>p</em> = 0.0004) in overweight monkeys. The insulin-lowering effects and enhanced insulin sensitivity were maintained even after reintroduction of normal feeding. By day 126, the sustained increase in lymphocyte-to-neutrophil ratio was exclusive to the continuous intermittent fasting group (HW-IF-IF), suggesting a potential immunomodulatory effect of prolonged fasting. Longitudinal gut microbiota analysis indicated that the gut microbiota structure underwent limited compositional changes. Nevertheless, time-dependent enrichments emerged in several genera, including <em>Ruminococcus</em>, <em>Eubacterium_hallii_group</em>, and <em>Monoglobus</em>. Serum metabolomics unveiled pronounced time-dependent alterations in circulating metabolites.<h3>Conclusion</h3>These findings elucidate physiological and metabolic adaptations to specified IF-refeeding regimen in cynomolgus monkeys and establish a framework for mechanistic studies of fasting-induced metabolic responses in non-human primates.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"8 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147384137","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 : 2026-03-06DOI: 10.1016/j.jare.2026.02.055
Xinyi Han, Lingwei Ma, Jiahui Dai, Dong Gao, Wei Wang
Background
Precancerous lesions are pivotal intermediates in tumorigenesis, creating critical windows for early detection and intervention. However, research has been hindered by limited clinical samples, pronounced molecular heterogeneity, and the absence of models that faithfully mirror in vivo pathology. Organoids have emerged as a powerful solution, preserving patient-specific genetic, phenotypic, and microenvironmental features while enabling long-term culture and functional interrogation.
Aim of review
This review aims to systematically synthesize recent advances in organoid-based modeling of precancerous lesions. We summarize the latest progress in organoid construction strategies, validation frameworks, and multidimensional applications, including mechanistic dissection of precancerous evolution, biomarker discovery for early detection, and therapeutic screening for precision prevention. Furthermore, we highlight integrative approaches that combine CRISPR-mediated genome editing and single-cell multi-omics to enhance the fidelity, scalability, and clinical relevance of organoid systems in precancer research.
Key scientific concepts of review
Organoid technology is reshaping paradigms in precancer research by bridging fundamental biology with clinical translation, providing unprecedented tools for early detection, risk stratification, and personalized cancer prevention.
{"title":"Organoids revolutionizing precancer research","authors":"Xinyi Han, Lingwei Ma, Jiahui Dai, Dong Gao, Wei Wang","doi":"10.1016/j.jare.2026.02.055","DOIUrl":"https://doi.org/10.1016/j.jare.2026.02.055","url":null,"abstract":"<h3>Background</h3>Precancerous lesions are pivotal intermediates in tumorigenesis, creating critical windows for early detection and intervention. However, research has been hindered by limited clinical samples, pronounced molecular heterogeneity, and the absence of models that faithfully mirror <em>in vivo</em> pathology. Organoids have emerged as a powerful solution, preserving patient-specific genetic, phenotypic, and microenvironmental features while enabling long-term culture and functional interrogation.<h3>Aim of review</h3>This review aims to systematically synthesize recent advances in organoid-based modeling of precancerous lesions. We summarize the latest progress in organoid construction strategies, validation frameworks, and multidimensional applications, including mechanistic dissection of precancerous evolution, biomarker discovery for early detection, and therapeutic screening for precision prevention. Furthermore, we highlight integrative approaches that combine CRISPR-mediated genome editing and single-cell multi-omics to enhance the fidelity, scalability, and clinical relevance of organoid systems in precancer research.<h3>Key scientific concepts of review</h3>Organoid technology is reshaping paradigms in precancer research by bridging fundamental biology with clinical translation, providing unprecedented tools for early detection, risk stratification, and personalized cancer prevention.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"407 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359953","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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