Journal of Advanced Research最新文献

{"title":"The clinicopathologic features of fulminant myocarditis","authors":"Guanglin Cui, Jiali Nie, Huihui Li, Luyun Wang, Kun Miao, Chunxia Zhao, Jiangang Jiang, Dao Wen Wang","doi":"10.1016/j.jare.2025.06.040","DOIUrl":"https://doi.org/10.1016/j.jare.2025.06.040","url":null,"abstract":"<h3>Background</h3>Fulminant myocarditis (FM) is the most severe form of myocarditis, characterized by rapid clinical progression and circulatory instability. However, its pathological features and their relationship to clinical presentation are not well understood<h3>Objectives</h3>This study aims to provide an overview of the clinicopathologic features of FM.<h3>Methods</h3>A total of 80 patients with FM were enrolled between January 2021 and September 2022 in Wuhan, China. Endomyocardial biopsies and subsequent histochemical staining were performed on all patients who were followed up for 3 months. The pathological features of the myocardium were described. The relationship between myocardial inflammatory cell infiltration and clinical presentation was analyzed.<h3>Results</h3>According to hematoxylin and eosin staining, 76 out of 80 patients with FM were diagnosed with lymphocytic myocarditis, while 4 were diagnosed with eosinophilic myocarditis. Microscopically, various forms of cell degeneration were observed, especially myocardial edema and cardiomyocyte necrosis. Histochemical analysis indicated that innate immune cells (primarily macrophages and neutrophils) predominated in the acute stage of FM. Proper treatment with immunomodulatory agents, such as glucocorticoids and immunoglobulin, promoted macrophage polarization into the M2 subtype. A high density of total inflammatory cell infiltration was associated with elevated levels of inflammatory biomarkers (hs-CRP and ESR) and more severe circulatory deterioration, which necessitated more frequent use of IABP, ECMO, and pacemakers.<h3>Conclusions</h3>To date, this largest cohort of histochemical analyses of FM, based on endomyocardial biopsy samples, has revealed dominant infiltration of innate immune cells in the early stage, followed by lymphocytes. This finding suggests that the activation of innate immunity is the initial mechanism triggering the cytokine storm in FM. The results also support the beneficial effects of immunomodulatory therapy using glucocorticoids and immunoglobulins rather than immunosuppression by promoting M2 macrophage polarization. This study was registered at <span><span>https://clinicaltrials.gov/study/NCT03268642</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"93 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311763","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":"Perfluorooctane sulfonic acid impairs spermatogenesis via the liver-gut microbiota-testis axis: a central role of chenodeoxycholic acid metabolism","authors":"Wang Yang, Peng Zou, Shijun He, Haonan Cui, Zeyu Yang, Huihui An, Qing Chen, Wei Huang, Hong Guo, Jinyi Liu, Xi Ling, Jia Cao, Lin Ao","doi":"10.1016/j.jare.2025.06.037","DOIUrl":"https://doi.org/10.1016/j.jare.2025.06.037","url":null,"abstract":"<h3>Introduction</h3>Perfluorooctane sulfonic acid (PFOS) as a global contaminant is ubiquitously presented in the environmental media and human body. The association between PFOS exposure and reduced male fertility has been recently discovered. However, the relevant mechanism remains unexplored.<h3>Objectives</h3>Our study aimed to investigate the effect and mechanism of PFOS exposure on male reproductive function.<h3>Methods</h3>In a murine PFOS exposure model, single-nucleus transcriptome sequencing was performed to delineate the transcriptomic landscape of mouse testes at the single-cell resolution. We examined the serum metabolomic profile and conducted in-depth analysis of hepatic transcriptome datasets to explore the metabolic connections between liver and testis under PFOS exposure. Through integrating chenodeoxycholic acid intervention, fecal microbiota transplantation (FMT), metagenomic sequencing, testicular metabolome, <em>Ligilactobacillus murinus</em> (<em>L. murinus</em>) metabolome, and administration of <em>L. murinus</em>, we confirmed the role of the liver-gut microbiota-testis axis and screened the critical gut microbiota involved in PFOS-mediated spermatogenic disorders.<h3>Results</h3>The results showed that PFOS exposure led to spermatogenic arrest and abnormal spermatogenic microenvironment in the mouse testis. The PFOS-repressed hepatic chenodeoxycholic acid (CDCA) synthesis contributed to the reduced serum/testicular levels of essential fatty acid (linoleic acid) and lipid-soluble vitamins (retinol, vitamin D3), which was responsible for the spermatogenic arrest. Beyond this, PFOS-mediated impaired CDCA production decreased the abundance of gut <em>L. murinus</em>, which affected spermatogenesis through the potential involvement of aspartic acid metabolism. For the first time to our knowledge, we comprehensively assessed the effects of PFOS exposure on the spermatogenic process and elucidated the unrecognized role of liver-gut microbiota-testis axis in PFOS-induced abnormal spermatogenesis.<h3>Conclusions</h3>The unveiled organ crosstalks provide new insights into the metabolism-disrupting properties, hepatotoxicity, and reproductive toxicity of PFOS, which may facilitate the development of molecule-, metabolite-, and microbe-based strategies for PFOS-induced metabolic diseases and reproductive disorders.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"37 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311708","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":"Therapeutic role of caveolin family in stem cell fate and development for management of chronic degenerative diseases: A scientometric study to an in-depth review","authors":"Ruishuang Ma, Shuang Wang, Yuan-Lu Cui, Han Zhang, Xiaopeng Chen, Jinbing Xie, Yue Li","doi":"10.1016/j.jare.2025.06.034","DOIUrl":"https://doi.org/10.1016/j.jare.2025.06.034","url":null,"abstract":"<h3>Background</h3>Caveolins (CAV), a family of integral membrane proteins, are involved in regulating stem cell fate, which are critical for tissue repair and regeneration. Drawing from scientometric studies and comprehensive research, this review investigates the mechanisms by which CAV regulates stem cell fate can improve the efficiency and accuracy of stem cell therapy in treating chronic degenerative diseases (CDD). For instance, CAV1 inhibits neuronal differentiation of neural stem/progenitor cells (NSCs/NPCs) by downregulating VEGF, p44/42MAPK phosphorylation and NeuroD1 signaling pathway following ischemic stroke, while CAV3 interacts with MG53 to enhance the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) in diabetic wound healing by activating the eNOS/NO signaling pathway.<h3>Aim of review</h3>Our review aims to elaborate the impact of CAV on diverse stem cell populations and regulatory mechanisms, as well as point out novel insights brought by CAV and stem cell therapy in the management of CDD, such as stroke, Alzheimer’s disease (AD), Parkinson’s disease (PD), diabetes, pulmonary arterial hypertension (PAH), breast cancer and liver cancer.<h3>Key scientific concept of review</h3>Based on scientometrics studies, this review synthesizes current analyses of the CAV family’s role in determining the fate of various stem cell populations, thereby providing new perspectives for the prevention and treatment of CDD.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"23 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311704","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":"S-sulfhydration: Novel insights into the antioxidant and antiinflammation in age-related diseases","authors":"Fei Liu, Lan Li, Longhui Yuan, Jingchao Yang, Xi Tang, Jingping Liu, Shuyun Liu, Younan Chen, Yanrong Lu, Jingqiu Cheng, Yujia Yuan","doi":"10.1016/j.jare.2025.06.038","DOIUrl":"https://doi.org/10.1016/j.jare.2025.06.038","url":null,"abstract":"<h3>Background</h3>Hydrogen sulfide (H₂S) and hydrogen polysulfide-induced S-sulfhydration are critical posttranslational modifications that specifically target cysteine residues within proteins. Degenerative diseases are often characterized by oxidative stress and inflammaging, ultimately leading to progressive organ dysfunction. Emerging evidence underscores the essential role of S-sulfhydration in modulating mitochondrial synthesis, energy metabolism, and cellular homeostasis during aging. However, the intricate pathways and molecular regulators that connect S-sulfhydration to degenerative pathologies remain insufficiently elucidated.<h3>Aim of review</h3>This review aims to delineate the biological significance of S-sulfhydration in the context of age-associated degenerative disorders especially in redox balance and inflammatory response, including neurodegenerative diseases, osteoarthrosis, osteoporosis, and age-related renal pathologies. In addition, the redox-adaptive S-sulfhydration and clinical applications based on S-sulfhydration-related delivery strategies are proposed, which may reveal novel therapeutic interventions in combating aging.<h3>Key scientific concepts of review</h3>This review provides a detailed synthesis of the cellular and molecular mechanisms by which S-sulfhydrated target proteins mitigate senescence phenotypes through antioxidative and anti-inflammatory pathways. Nonetheless, the dual role of S-sulfhydration highly depends on threshold-dependent signaling correlated with H₂S synthetase. Moreover, the dynamic compensatory mechanism of S-sulfhydration plays a critical role in the interaction between oxidative stress and inflammatory stress during the aging process, which identifies S-sulfhydration-mediated redox homeostasis as a promising avenue for therapeutic interventions aimed at mitigating the progression of degenerative diseases.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"18 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305257","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":"Root-derived low molecular weight organic acids modulate keystone microbial taxa impacting plant phosphorus acquisition","authors":"Jie Zheng, Guangping Shi, Francisco Dini-Andreote, Yeyuping Yang, Yuji Jiang","doi":"10.1016/j.jare.2025.06.032","DOIUrl":"https://doi.org/10.1016/j.jare.2025.06.032","url":null,"abstract":"<h3>Introduction</h3>Low-molecular-weight organic acids (LMWOAs) present in root exudates modulate the assembly and function of phosphorus (P)-mobilizing bacteria in the rhizosphere. Nonetheless, relatively little is known about how specific LMWOAs affect the structure of rhizosphere microbes associated with P cycling.<h3>Objectives</h3>This study aimed to elucidate the mechanisms by which LMWOAs affect the recruitment of P-mobilizing bacterial communities, with implications for P bioavailability and plant P uptake.<h3>Methods</h3>The <em>pqqC</em> and <em>phoD</em> bacterial genes, along with root-derived LMWOAs, were profiled using amplicon sequencing and non-targeted metabolomics. The mechanisms underlying the stimulation of P-mobilizing bacteria for soil P mobilization and plant P uptake were investigated through <em>in vitro</em> and pot experiments, complemented by transcriptomics and proteomics.<h3>Results</h3>Field data indicated that manure amendment increased the soil labile-P fraction and P bioavailability. Additionally, it was observed that root-derived aliphatic and aromatic LMWOAs modulated the structure, diversity, and abundance of <em>pqqC</em> and <em>phoD</em> genes, correlating with the expression levels of phosphate transporters and acid phosphatases in maize roots. <em>In vitro</em> and pot experiments validated the effects of 2-hydroxycinnamic, syringic, isoferulic, and alpha-ketoglutaric acids on the keystone bacteria (<em>Burkholderia</em>, <em>Pseudomonas</em>, <em>Mesorhizobium</em>, and <em>Sinorhizobium</em>). These molecules enhanced the diversity and abundance of <em>pqqC</em> and <em>phoD</em> genes, affecting maize root morphology, plant gene expression, and protein synthesis.<h3>Conclusion</h3>This study elucidated the intricate interactions between maize root exudates and P-mobilizing bacteria. The results provide new avenues for exploring root-derived LMWOAs as signaling molecules to optimize synthetic biological strategies for sustainable agriculture.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"37 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305275","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":"Probiotics and triglyceride manipulation: potential implications for alleviating hypertriglyceridemia","authors":"Mingliang Zhang, Weimin Jiang, Jie Yin, Dingfu Xiao","doi":"10.1016/j.jare.2025.06.036","DOIUrl":"https://doi.org/10.1016/j.jare.2025.06.036","url":null,"abstract":"<h3>Background</h3>Hypertriglyceridemia is one of the most prevalent lipid abnormalities encountered in clinical practice. Although many monogenic disorders causing severe hypertriglyceridemia have been identified, in most patients, triglyceride elevations result from a combination of multiple genetic variations with small effects and environmental factors. Common secondary causes include obesity, uncontrolled diabetes, alcohol abuse, high-fat foods, and the use of various commonly prescribed drugs. Notably, manipulating the gut microbiota through probiotic intervention may reduce triglyceride levels by targeting intestinal lipid absorption and host lipid metabolism.<h3>Aim of review</h3>This paper reviews recent animal and human studies on probiotic interventions, summarizing the mechanisms through which probiotics reduce triglyceride levels and exploring the potential of next-generation probiotics in alleviating hypertriglyceridemia.<h3>Key scientific concepts of review</h3>To discuss the link between gut microbiota and hypertriglyceridemia and the next generation of probiotics with the potential to reduce hypertriglyceridemia. Meanwhile, we also elucidate the mechanisms through which probiotics and their metabolites, such as short-chain fatty acids and bile acids, mediate multiple pathways to reduce triglyceride levels. Finally, the challenges and prospects of the application of probiotics were prospected.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"51 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305255","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":"Lactobacillus johnsonii-derived extracellular vesicles carrying GAPDH protect against ulcerative colitis through modulating macrophage polarization","authors":"Shiyu Tao, Mengzhen Song, Jinping Fan, Feng Zhu, Tengfei Lv, Hong Wei","doi":"10.1016/j.jare.2025.06.035","DOIUrl":"https://doi.org/10.1016/j.jare.2025.06.035","url":null,"abstract":"<h3>Introduction</h3>Ulcerative colitis (UC) is a major inflammatory condition worldwide.<h3>Objectives</h3>The purpose of this study was to investigate the potential contribution of <em>Lactobacillus johnsonii</em> against UC from the perspective of gut microbiota-macrophage-host interactions.<h3>Methods</h3><em>L. johnsonii</em> abundance in UC patients and colitis mice was evaluated by genomic sequencing. SPF and macrophage-depleted mice were employed to explore the effects of <em>L. johnsonii</em> and its products on colitis. An <em>in vitro</em> macrophage and intestinal epithelial cell co-culture system was constructed. Proteins in extracellular vesicles (EVs) were identified by proteomic analyses, and host signaling pathways were analyzed with transcriptomic analyses.<h3>Results</h3><em>L. johnsonii</em> abundance was found to be associated with macrophage polarization and intestinal barrier function in human UC patients and mice of a colitis model. <em>L. johnsonii</em> and its derived EVs alleviate colitis in mice in a macrophage-dependent manner. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a protein in EVs derived from <em>L. johnsonii</em>, counteracts colitis <em>in vitro</em> and <em>in vivo</em> by regulating macrophage phenotype. GAPDH enhances anti-inflammatory macrophage polarization by inhibiting the MAPK-STAT3 axis. Macrophage-secreted EVs enhances intestinal barrier function in colitis mice by blocking the TLR4 pathway. Protein components in macrophage-derived EVs contribute to colitis remission and intestinal barrier protection.<h3>Conclusion</h3>GAPDH originating in <em>L. johnsonii</em>-derived EVs alleviates colitis and improves intestinal barrier by inhibiting STAT3 in macrophages. EVs created from <em>L. johnsonii</em> are a potential novel treatment strategy for UC.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"43 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296240","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":"Three-dimensional multimodal imaging for predicting early recurrence of hepatocellular carcinoma after surgical resection","authors":"Jie Peng, Jiaren Wang, Hongbo Zhu, Pu Jiang, Ji Xia, Hao Cui, Chang Hong, Lin Zeng, Ruining Li, Yan Li, Shengxing Liang, Qijie Deng, Huangying Deng, Hengtian Xu, Hanzhi Dong, Lushan Xiao, Li Liu","doi":"10.1016/j.jare.2025.06.031","DOIUrl":"https://doi.org/10.1016/j.jare.2025.06.031","url":null,"abstract":"<h3>Background</h3>High tumor recurrence after surgery remains a significant challenge in managing hepatocellular carcinoma (HCC). We aimed to construct a multimodal model to forecast the early recurrence of HCC after surgical resection and explore the associated biological mechanisms.<h3>Materials and methods</h3>Overall, 519 patients with HCC were included from three medical centers. 433 patients from Nanfang Hospital were used as the training cohort, and 86 patients from the other two hospitals comprised validation cohort. Radiomics and deep learning (DL) models were developed using contrast-enhanced computed tomography images. Radiomics feature visualization and gradient-weighted class activation mapping were applied to improve interpretability. A multimodal model (MM-RDLM) was constructed by integrating radiomics and DL models. Associations between MM-RDLM and recurrence-free survival (RFS) and overall survival were analyzed. Gene set enrichment analysis (GSEA) and multiplex immunohistochemistry (mIHC) were used to investigate the biological mechanisms.<h3>Results</h3>Models based on hepatic arterial phase images exhibited the best predictive performance, with radiomics and DL models achieving areas under the curve (AUCs) of 0.770 (95 % confidence interval [CI]: 0.725–0.815) and 0.846 (95 % CI: 0.807–0.886), respectively, in the training cohort. MM-RDLM achieved an AUC of 0.955 (95 % CI: 0.937–0.972) in the training cohort and 0.930 (95 % CI: 0.876–0.984) in the validation cohort. MM-RDLM (high vs. low) was notably linked to RFS in the training (hazard ratio [HR] = 7.80 [5.74 − 10.61], <em>P</em> &lt; 0.001) and validation (HR = 10.46 [4.96 − 22.68], <em>P</em> &lt; 0.001) cohorts. GSEA revealed enrichment of the natural killer cell-mediated cytotoxicity pathway in the MM-RDLM low cohort. mIHC showed significantly higher percentages of CD3-, CD56-, and CD8-positive cells in the MM-RDLM low group.<h3>Conclusion</h3>The MM-RDLM model demonstrated strong predictive performance for early postoperative recurrence of HCC. These findings contribute to identifying patients at high risk for early recurrence and provide insights into the potential underlying biological mechanisms.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"14 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305300","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":"Age-dependent elevation of Nr4a1 attenuates PI3K/AKT/GSK3β pathway and mediates tau hyperphosphorylation and cognitive impairments","authors":"Ling Lei, Qian Guo, Yilei Cheng, Yuran Gui, Wensheng Li, Yiheng Zhao, Zhendong Xu, Yong Luo, Gang Wu, Jian-Zhi Wang, Rong Liu, Hong-Lian Li, Xiaochuan Wang","doi":"10.1016/j.jare.2025.06.033","DOIUrl":"https://doi.org/10.1016/j.jare.2025.06.033","url":null,"abstract":"<h3>Introduction</h3>Tau hyperphosphorylation exhibited in Alzheimer’s brains is also commonly observed in aging process, however, the molecular mechanism underlying tau hyperphosphorylation in aging is largely unknown. The nuclear receptor subfamily 4 group A (Nr4a1) has been implicated in various pathophysiological processes including neurodegeneration, and was found to be increased in Alzheimer’s brains.<h3>Objectives</h3>Our study aims to investigate whether and how Nr4a1 promotes age-related tau hyperphosphorylation and cognitive decline.<h3>Methods</h3>Firstly, we examined Nr4a1 levels in hippocampus of Alzheimer’s patients, SAMP8 and aged mice. Tau phosphorylation levels and cognitive function were evaluated in hippocampal Nr4a1-overexpressed wild-type mice. Bulk RNA sequencing was performed to gain insight into the molecular mechanism by which elevated Nr4a1 levels drive tau hyperphosphorylation. Lenti-shNr4a1 was used to knockdown Nr4a1 in senescent neurons and hippocampus of SAMP8 mice, further, tau phosphorylation levels and cognitive function were evaluated. Molecular docking studies were conducted to explore the interaction between Nr4a1 and AKT.<h3>Results</h3>Our findings revealed that Nr4a1 expression is elevated in the hippocampus of Alzheimer’s patients, as well as in the hippocampi of SAMP8 mice and aged mice. Notably, in SAMP8 mice, Nr4a1 expression increased in an age-dependent manner, suggesting a positive correlation between Nr4a1 levels and aging. Further investigation showed that hippocampal overexpression of Nr4a1 in wild-type mice led to tau hyperphosphorylation and cognitive dysfunction, which could be rescued by Nr4a1 knockdown in SAMP8 mice. By means of bulk RNA sequencing, we demonstrated that Nr4a1 induced tau hyperphosphorylation through the inhibition of PI3K/AKT/GSK-3β pathway. Furthermore, blocking Nr4a1-AKT interactions using competitive peptides reversed tau hyperphosphorylation.<h3>Conclusion</h3>These results supported the hypothesis that age-dependent upregulation of Nr4a1 attenuated PI3K/AKT/GSK-3β pathway, leading to tau hyperphosphorylation and cognitive decline. Nr4a1 may represent a promising therapeutic target for mitigating age-related cognitive impairments.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"28 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305361","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":"GhGLDH35A gene-mediated ROS homeostasis and stomatal movement via the ascorbic acid pathway confers alkaline stress tolerance","authors":"Yapeng Fan, Ning Wang, Shuai Wang, Zhining Yang, Xiao Chen, Xuke Lu, Hui Huang, Xiugui Chen, Lanjie Zhao, Menghao Zhang, Yuping Sun, Junjuan Wang, Lixue Guo, Lidong Wang, Ruize Song, Jing Wang, Xinrui Zhang, Xin Yu, Yi Liu, Xuerong Zhou, Wuwei Ye","doi":"10.1016/j.jare.2025.06.018","DOIUrl":"https://doi.org/10.1016/j.jare.2025.06.018","url":null,"abstract":"<h3>Introduction</h3>Ascorbic acid (AsA) is involved in plant responses to various abiotic stresses. However, its specific function in alkaline stress tolerance remains poorly understood. The L-galactono-1,4-lactone dehydrogenase (<em>GLDH</em>) gene is crucial for AsA synthesis, yet the precise role of <em>GLDH</em> in modulating plant resistance to alkaline stress has not been comprehensively characterized.<h3>Objectives</h3>To investigate the role of <em>GLDH</em> genes in enhancing tolerance to alkaline stress.<h3>Methods</h3>Bioinformatics analysis of the <em>GLDH</em> gene family members was conducted, and an evolutionary tree was constructed using MEGA software. <em>Cis</em>-acting elements and gene structures were analyzed using TBtools. Gene expression levels were quantified by qRT-PCR, while the function of the <em>GhGLDH35A</em> gene was validated through VIGS (Virus-induced gene silencing) in cotton, heterologous overexpression in <em>Arabidopsis thaliana</em>, and complementation assays in yeast.<h3>Results</h3>Our study investigated the effects of salt-alkaline stress on cotton and found that alkaline stress caused significantly more severe damage than salt stress. The <em>GLDH</em> family genes were identified and analyzed, revealing a high degree of evolutionary conservation. Most <em>GhGLDH</em> genes exhibited a positive response to alkaline stress and were regulated by light. Among them, <em>GhGLDH35A</em>, which is highly expressed within the <em>GLDH</em> family, was found to play a key role in conferring tolerance to alkaline stress. Subcellular localization analysis indicated that GhGLDH35A is localized in the mitochondria. Silencing of <em>GhGLDH35A</em> in cotton resulted in reduced tolerance to alkaline stress, disruption of ROS homeostasis, and impairment of photosynthesis and stomatal function. Conversely, overexpression of <em>GhGLDH35A</em> in <em>Arabidopsis</em> enhanced alkaline stress resistance by elevating AsA levels, increasing antioxidant enzyme activities to enhance ROS scavenging, sustaining photosynthesis, and promoting stomatal closure. Furthermore, heterologous expression of <em>GhGLDH35A</em> in yeast also improved its tolerance to alkaline stress.<h3>Conclusions</h3><em>GhGLDH35A</em> positively regulates alkaline stress tolerance by enhancing antioxidant defenses and regulating stomatal movement.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"178 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144296241","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}