Journal of Advanced Research最新文献

{"title":"MTHFR variant links homocysteine metabolism and endothelial cell dysfunction by targeting mitophagy in human thoracic aortic dissection patient induced pluripotent stem cell (iPSC) models","authors":"You Yu, Lianbo Shao, Meng Zhang, Xingyou Guo, Yihuan Chen, Han Shen, Xiaomei Teng, Jingze Zhu, Miao Yu, Shijun Hu, Zhenya Shen","doi":"10.1016/j.jare.2025.02.032","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.032","url":null,"abstract":"<h3>Aims</h3>Genetics and environmental cues boost the development of human diseases. Methylenetetrahydrofolate reductase (<em>MTHFR</em>) is involved in the metabolism of homocysteine, and a common variant rs1801133 of <em>MTHFR</em> has been reported in human cardiovascular diseases. This study aims to providing a novel strategy for patient stratification with specific genetic and metabolic screening, finally for personalized healthcare for patients with thoracic aortic dissection.<h3>Methods and results</h3>We corrected the <em>MTHFR</em> variant to generate an isogenic control iPSC line (Isogenic-iPSC) with CRISPR/Cas9 method, and this isogenic-iPSC shared the same other genetic information with our previously established MTHFR-iPSC line, providing a promising approach for analysis the phenotype and mechanism of rs1801133. During the direct differentiation of endothelial cells from both iPSC lines, rs1801133 variant did not affect the endothelial cell fate determination. Without homocysteine, this variant has little effect on endothelial cell function. While administration of homocysteine, the MTHFR-iPSC derived endothelial cells exhibited disrupted mitophagy, increased cell apoptosis and decreased cell viability. Bulk RNA-seq data indicated LAMP3 is a target of homocysteine, activation of LAMP3 might contribute to homocysteine induced the disruption of mitochondrial structure and cell apoptosis. With chemical compounds screening, kaempferol ameliorated the homocysteine-induced cell toxicity by restoring the mitochondrial structure. The direct relationship between homocysteine metabolism and MTHFR rs1801133 variant was investigated, and the molecular target for homocysteine and translational perspective has also been demonstrated.<h3>Conclusions</h3>Collectively, this study provided the direct evidence of a specific genetic variant in <em>MTHFR</em> and homocysteine metabolism. Investigating the molecular mechanism of homocysteine activated LAMP3 on endothelial cell dysfunction and mitophagy could provide novel insights for targeted disease prevention and improving individual outcomes.<h3>TRANSLATIONAL PERSPECTIVE</h3>Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease with a high mortality, lacking effective medical treatment and early diagnosis. Endothelial cells dysfunction has been considered into the development of TAD. Here, we show that MTHFR variant is responsible for the elevated homocysteine in iPSC-ECs, and disrupted mitochondrial structures by homocysteine significantly impaired endothelial function. Understanding the mechanism and translational medicine of homocysteine-induced endothelial toxicity in human with <em>MTHFR</em> variant could benefit the novel strategy for prevention and vessel protection against metabolism injury. Meanwhile, targeting mitophagy and application of small molecule, such as kaempferol, also provide an insight for endothelial protection.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"21 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485859","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":"Deep-DPC: Deep learning-assisted label-free temporal imaging discovery of anti-fibrotic compounds by controlling cell morphology","authors":"Xu-dong Xing, Xiang-yu Yan, Yan-wei Tan, Yang Liu, Yi-xin Cui, Chun-ling Feng, Yu-ru Cai, Han-lin Dai, Wen Gao, Ping Zhou, Hui-ying Wang, Ping Li, Hua Yang","doi":"10.1016/j.jare.2025.02.028","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.028","url":null,"abstract":"<h3>Introduction</h3>Fibrosis can damage the normal function of many organs, such as cardiac function, for which no effective clinical therapies exist. However, traditional approaches to anti-fibrosis drug discovery have primarily focused on the final biological indicators, often overlooking the dynamic morphological changes during fibrosis progression. Here, we present a novel approach, <em>deep-DPC</em>, which integrates label-free, time-series digital phase contrast (DPC) imaging with cell morphology analysis and unsupervised machine learning to dynamically control and monitor cell morphology.<h3>Objectives</h3>This method enables discrimination between resting and activated fibrocytes and facilitates the discovery of non-invasive labeled anti-fibrotic lead compounds.<h3>Methods</h3>The <em>deep-DPC</em> comprises two major steps: (1) preliminary analysis by Harmony 4.9 software and (2) image classification <em>via</em> a neural network. For the experiment dataset, label-free time-series imaging was acquired from each well at 10 × magnification using the high-content imaging system, equipped with a high-speed charge-coupled device (CCD) camera. Dual-channel output images were generated through the imaging system, with one channel for bright-field and the other for DPC imaging, captured at 30-minute intervals Firstly, applying the anti-fibrotic cell model as a case, a label-free time-series DPC imaging was developed by combining cell morphological analysis and deep learning, and its stability was verified by training with 12,000 images. Furthermore, the Application of <em>deep-DPC</em> in the discovery of anti-fibrotic lead compounds.<h3>Results</h3>Using the <em>deep-DPC</em> platform, over 100,000 images generated from 1,400 compounds were processed, identifying Neo-Przewaquinone A as a potent anti-fibrosis agent. Neo-Przewaquinone A exerts its effects by inhibiting TGF-β receptor I, thereby maintaining cells in a resting state and arresting the cell cycle.<h3>Conclusion</h3>The <em>deep-DPC</em> offers a promising strategy for fibrosis assessment by combining deep learning with dynamic cell morphology analysis based on time-series DPC images. Additionally, the platform holds potential as a novel therapeutic approach for anti-myocardial fibrosis by regulating cell morphology.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"5 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477455","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":"NCX1 interacts with TRPA1 to promote cell proliferation and tumor growth of colon cancer via disruption of calcium homeostasis","authors":"Liyong Zhou, Guolong Zhou, Junhui Li, Ruihong Guo, Hui Dong","doi":"10.1016/j.jare.2025.02.031","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.031","url":null,"abstract":"<h3>Introduction</h3>Aberrant Ca²⁺ signaling plays a critical role in the hallmark of cancer, but its regulatory mechanisms in tumorigenesis remain largely unclear. Na⁺/Ca²⁺ exchanger 1 (NCX1) functions as a bidirectional Na⁺ and Ca²⁺ transporter, operating in either Ca²⁺ entry or exit mode, while the transient receptor potential ankyrin 1 (TRPA1) serves as a Ca²⁺-permeable channel. Both play crucial roles in maintaining normal homeostasis of cytosolic Ca²⁺ ([Ca²⁺]_cyt). Although each of them has been implicated in some tumorigenesis, the potential coordination between NCX1 and TRPA1 in the pathogenesis of colon cancer (CC) remains unexplored.<h3>Objectives</h3>We investigated the impact of NCX1- and TRPA1-mediated Ca²⁺ signaling on CC and the underlying mechanisms.<h3>Methods</h3>The cell experiments were conducted using the human normal colonic epithelial cell line (HCoEpiC) and human colon cancer cell lines (Caco-2, SW620, and DLD-1). We performed stable transfection to knock down NCX1 or TRPA1 genes and employed CCK8, colony formation, and flow cytometry assays to assess cell proliferation. We employed RT-qPCR, Western blotting, immunofluorescence and co-immunoprecipitation assays to explore the expression and regulatory relationship between NCX1 and TRPA1. Calcium and sodium assays were used to determine [Ca²⁺]_cyt and [Na⁺]_cyt. Finally, we used the xenografted tumor model to verify their impact on CC development <em>in vivo</em>.<h3>Results</h3>NCX1 and TRPA1 were parallelly over-expressed, co-localized, and bound, and their functional activities were enhanced in human CC cells. NCX1 functions in Ca²⁺ exit mode to expel [Ca²⁺]_cyt, in which TRPA1 function was clearly verified as well. Moreover, when the Ca²⁺ exit mode of NCX1 was inhibited, TRPA1 activation resulted in a larger amount of [Ca²⁺]_cyt to suppress cell proliferation through inhibiting ERK1/2 and β-catenin phosphorylation. NCX1 or TRPA1 knockdown significantly diminished tumor growth <em>in vivo</em>.<h3>Conclusion</h3>TRPA1 channels couple with the Ca²⁺ exit mode of NCX1 to maintain a moderate increase in [Ca²⁺]_cyt in CC cells, thereby promoting CC cell proliferation and tumor growth through ERK1/2 and β-catenin phosphorylation. Consequently, the NCX1/TRPA1 coupling may serve as an innovative target for preventing and treating CC.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"39 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485675","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":"Digital twin-driven operational CycleGAN-based multiple virtual-physical mappings for remaining useful life prediction under limited life cycle data","authors":"Quanning Xu, Zihao Lei, Shulong Gu, Guangrui Wen, Yu Su, Zhifen Zhang, Jing Huang, Rui Qin","doi":"10.1016/j.jare.2025.02.029","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.029","url":null,"abstract":"Accurately predicting the remaining useful life (RUL) of complex equipment plays a vital role in maintaining modern manufacturing systems’ operational safety and reliability. This challenge has attracted considerable interest within the domain of intelligent operation and maintenance. However, the lack of high-quality, comprehensive lifecycle data in industrial environments is a major barrier to developing and deploying intelligent RUL prediction algorithms. Digital twin technology offers a novel solution by utilizing virtual resources to provide insights into the operation and maintenance of physical entities, thus addressing the issue of data insufficiency. This study presents an innovative lifecycle digital twin model and RUL prediction framework, based on operational CycleGAN with multiple virtual-physical mappings. First, a six-degree-of-freedom dynamic model of the bearing is developed as a digital representation. Subsequently, the mapping relationships between measured signals and bearing parameters are explored. The KAN mapping network is employed to forecast the evolutionary patterns of bearing parameters, enabling the construction of a full-lifecycle dynamic model. A self-organized neural operator is then integrated into the CycleGAN network to enable iterative updates and corrections of twin signals. This is achieved through the interaction of fault and environmental information across virtual and physical domains. Experimental results demonstrate that the generated lifecycle twin data exhibit a high degree of similarity and consistency with measured data distributions. The proposed method is compatible with advanced RUL prediction models, allowing accurate predictions even with limited lifecycle data.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"26 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485860","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":"Cuticle thickening mediates insecticide penetration resistance in Spodoptera litura","authors":"Bingjie Wang, Minghui Yi, Mengyu Wang, Hengji Wang, Zi Tang, Hui Zhao, Peng Wei, Xiaolan Liao, Wenxin Xue, Lang Pan, Li Shi","doi":"10.1016/j.jare.2025.02.027","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.027","url":null,"abstract":"<h3>Introduction</h3>Long-term and extensive use of chemical pesticides has led to the development of resistance in many important agricultural pests. The mechanisms of resistance formation in pests are complex and variable, and unraveling the resistance mechanisms is the key to control resistant pests. Insect cuticle, as the first line of defense for insecticides, plays a non-negligible role in insecticide penetration resistance. Although penetration resistance is widespread in insects, the multiple molecular mechanisms that impede insecticide penetration are unclear, especially in <em>Spodoptera litura</em>.<h3>Objectives</h3>This study aims to reveal the molecular mechanisms of insecticide penetration resistance in <em>S. litura</em>.<h3>Methods</h3>The structure and thickness of cuticle were analyzed by TEM, and the role of cuticle in penetration resistance was determined by different application methods. The molecular mechanism of cuticular proteins overexpression was analyzed using RNAi, TEM, dual-luciferase assay and EMSA from cis- and <em>trans</em>-acting factors. In addition, the relationship between the chitin synthetic pathway and insecticide resistance was explored through enzyme activity, inhibitor assay, molecular docking and RNAi. Furthermore, the role of 20E in penetration resistance was analyzed.<h3>Results</h3>The cuticle of the resistant populations was significantly thickened and accompanied by extrusion, which contributed significantly to indoxacarb resistance. Constitutive upregulation of <em>trans</em>-acting factor <em>SlituFTZ-F1</em> co-regulates the overexpression of <em>SlituCP26</em> with <em>cis</em>-acting elements in the <em>SlituCP26</em> promoter (74 bp insertion), affecting the cuticle thickness‑mediated indoxacarb penetration resistance. Meanwhile, the overexpression of key genes in the chitin synthesis pathway increased the chitin content, which combined with <em>SlituCP26</em> to participate in indoxacarb resistance. Moreover, 20E affected the <em>SlituFTZ-F1</em>-mediated regulatory pathway and chitin biosynthesis pathway in indoxacarb resistance.<h3>Conclusion</h3>This study comprehensively elucidated the molecular mechanism of cuticle thickening mediating penetration resistance to indoxacarb and confirmed its existence in the field populations of <em>S. litura</em>.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"14 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477457","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":"Enhancing maize resistance to Fusarium verticillioides through modulation of cell wall structure and components by ZmXYXT2","authors":"Yufang Xu, Yudong Fan, Lujie Liu, Jiansheng Cao, Junzhe Zhou, Enpeng Liu, Ruiqi Li, Peipei Ma, Wen Yao, Jianyu Wu, Tao Li, Huiyong Zhang","doi":"10.1016/j.jare.2025.02.023","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.023","url":null,"abstract":"<h3>Introduction</h3><em>Fusarium verticillioides</em> (<em>F. verticillioides</em>) is a prevalent phytopathogen that incites severe diseases in maize, resulting in substantial reductions in grain yield and quality. Despite its widespread impact, the genetic mechanisms underlying resistance to this pathogen remain elusive, with only a limited of resistant genes having been identified to date.<h3>Objectives</h3>Characterize the function of <em>ZmXYXT2</em> encoding a putative xylan xylosyltransferase in maize defense against <em>F. verticillioides</em>-induced diseases.<h3>Methods</h3>Real-time quantitative PCR and transitory transformation of maize protoplasts were conducted to analyze the expression pattern and subcellular localization of <em>ZmXYXT2</em>. The <em>zmxyxt2</em> mutant, sourced from an ethyl methanesulfonate mutagenesis library, and the <em>ZmXYXT2</em>-overexpressing plants, generated via <em>Agrobacterium tumefaciens</em>-mediated transformation, were utilized for artificial inoculation with <em>F. verticillioides</em> followed by disease severity assessments. Phenotypic assessments, cytological observations, analysis of cell wall components, and histochemical staining were performed to elucidate the regulatory mechanisms of <em>ZmXYXT2</em>.<h3>Results</h3>The absence of <em>ZmXYXT2</em> renders maize vulnerable to <em>F. verticillioides</em>-caused seedling blight, stalk rot, ear rot and seed rot, along with a notable increase in fumonisin B1 accumulation. Conversely, maize plants overexpressing <em>ZmXYXT2</em> exhibited significantly heightened immunity to these diseases. Moreover, overexpression of <em>ZmXYXT2</em> results in notable changes in the composition of maize cell walls, specifically increasing the levels of arabinose, xylose and ferulic acid. These alterations lead to cell wall thickening, effectively barring the intracellular invasion and colonization of <em>F. verticillioides</em>, thereby halting pathogen dissemination between cells. Intriguingly, maize plants overexpressing <em>ZmXYXT2</em> exhibit enhanced stem strength without compromising yield-related traits.<h3>Conclusion</h3><em>ZmXYXT2</em> provides maize with resistance to multiple diseases triggered by <em>F. verticillioides</em> and mitigates the accumulation of fumonisin B1<em>.</em> Our study presents a novel approach to bolster maize comprehensive resistance against <em>F. verticillioides</em>-induced diseases by modifying cell wall composition to strengthen its natural defenses.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"89 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471092","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":"Lipophagy acts as a nutritional adaptation mechanism for the filamentous entomopathogenic fungus Beauveria bassiana to colonize within the hosts","authors":"Jin-Li Ding, Ming-Guang Feng, Sheng-Hua Ying","doi":"10.1016/j.jare.2025.02.025","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.025","url":null,"abstract":"<h3>Introduction</h3>Metabolic adaptation to various nutrients is crucial for the pathogenic growth and virulence of filamentous fungal pathogens. Despite its importance, the mechanisms underlying fungal adaptation to nutrient shifts, especially at the subcellular level, remain incompletely understood.<h3>Objectives</h3>Our study aims to investigate the mechanisms involved in metabolic adaptation in filamentous fungi.<h3>Methods</h3>The filamentous entomopathogenic fungus <em>Beauveria bassiana</em> was used as a representative of filamentous fungi. Gene functional analyses were characterized via gene disruption and complementation. Vacuolar targeting of lipid droplets were determined with transmission electron microscopy and fluorescence microscopy. Protein interaction was determined with yeast-two hybridization and co-immunoprecipitation methods.<h3>Results</h3>The filamentous entomopathogenic fungus <em>Beauveria bassiana</em> was found to initiate autophagy, and further lipophagy, when transitioning from utilizing fatty acids to carbohydrates, while also proliferating in the host hemocoel. The disruption of three critical autophagy-related genes (<em>ATG</em>), specifically <em>BbATG1</em>, <em>BbATG8</em>, and <em>BbATG11</em>, hindered the vacuolar targeting of lipid droplets (LD) and worsened the impaired growth and dimorphism in fatty acid medium subjected to cell-wall perturbance stress. Notably, BbSun4, a protein containing a SUN4 domain, was required for lipophagy, as it tagged the lipid droplets. BbMcp, which features a methyl-accepting chemotaxis-like domain, engaged directly with both BbAtg8 and BbSun4, thereby enhancing the interaction between these proteins. It is important to note that BbMcp solely facilitated lipophagy during nutrient shifts rather than during starvation stress. The loss of lipophagy proved detrimental to the integrity of the fungal cytomembrane, growth, and overall development, ultimately leading to a marked reduction in virulence.<h3>Conclusion</h3>Lipophagy is a molecular pathway that consists of a selective autophagy receptor, a bridging factor, and Atg8, which is essential for fungal metabolic adaptation during colonizing within the host niches. This study deepens our understanding of the molecular mechanism underling the fungus-host interaction and vacuolar targeting pathways in selective autophagy.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"21 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143470836","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":"Toxicological mechanisms of carbon polymers in accelerating cognitive decline in Alzheimer’s disease","authors":"Zihe Qi, Juanjuan Cao, Jianghua Liu, Jian Chen, Shasha Chen, Luyao Zhang, Jingwen Xu, Di Wu, Yongning Wu, Guoliang Li","doi":"10.1016/j.jare.2025.02.017","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.017","url":null,"abstract":"<h3>Introduction</h3>Alzheimer’s disease (AD) is the primary cause of dementia and is emerging as a global threat to human health. Increased availability of processed food is identified as a crucial environmental risk factor underlying the prevalence of Alzheimer’s disease. Carbon polymers (CPs), as neo-formed substances and ubiquitous in thermally processed foods, the relationship between them and AD onset is remains unclear.<h3>Objectives</h3>The effect of CPs on AD onset was examined and the toxicological mechanisms of prolonged exposure to CPs derived from thermal processed foods on AD progression were comprehensively investigated using a scopolamine-induced neuroinflammatory cell models and the transgenic APPswe/PSEN1dE9 (APP/PS1) AD mouse.<h3>Methods</h3>The CPs were extracted from thermally processed foods and the effects of CPs exposure on oxidative stress in neuroinflammatory cells were evaluated using scopolamine-induced PC12 cells as a neuroinflammation model. Furthermore, APP/PS1 AD mice were used to validate the potential adverse impacts of prolonged exposure to CPs on AD progression through the Morris water maze and open field test. In addition, histopathological examination, including immunofluorescence, immunohistochemistry, Nissl staining, and H&amp;E, of the brain tissue in AD mice after chronic CPs treatment was performed to elucidate the underlying risk of dietary exposure to CPs on AD progression.<h3>Results</h3>Exposure to CPs enhanced oxidative damage in neuroinflammatory cells, as demonstrated by impaired mitochondrial function and activated NF-κB/MAPK signaling pathways. Further results from electron spin resonance substantiated the catalytic properties of CPs, which accelerated oxidative damage through promoting free radical generation. Using transgenic AD mice model, our findings also demonstrated that prolonged CPs exposure aggravated AD-associated pathology, as evidenced by increased amyloid-beta deposition and glial cell activation, ultimately accelerating cognitive decline.<h3>Conclusion</h3>These findings provide compelling evidence of the potential health risks associated with long-term dietary exposure to CPs and provide insight into the relationship between foodborne risk factors and neurodegenerative diseases.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"89 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451710","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":"Comprehensive multi-omics analyses exposes a precision therapy strategy that targets replication stress in hepatocellular carcinoma using WEE1 inhibition","authors":"Xing Jia, Xingxin Zhu, Shinuo Chen, Qiongzi Qiu, Wenfeng Song, Shiyu Zhang, Haijiang Dong, Zequn Li, Suchen Bian, Hao Wu, Haojiang Dai, Cheng Jin, Mengqiao Zhou, Chen Jun, Zefeng Xuan, Pengfei Liu, Qiufang Zeng, Haiyang Xie, Shusen Zheng, Penghong Song","doi":"10.1016/j.jare.2025.02.016","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.016","url":null,"abstract":"&lt;h3&gt;Introduction&lt;/h3&gt;Hepatocellular carcinoma (HCC) is an extremely heterogeneous malignancy with a poor prognosis, highlighting the need to target specific vulnerabilities within the tumor during treatment.&lt;h3&gt;Objectives&lt;/h3&gt;This study employs multi-omics analysis techniques to provide novel insights into personalized therapeutic strategies for HCC patients.&lt;h3&gt;Methods&lt;/h3&gt;We performed proteomic and transcriptomic sequencing on 178 and 94 clinical samples of primary HCC without prior treatment, respectively. We employed an unbiased Kinome CRISPR-Cas9 library screening approach to systematically evaluate and identify novel therapeutic strategies that specifically target replication stress (RS). The synergy between oxaliplatin and adavosertib was verified using in vitro and in vivo models, including hydrodynamic injection, patient-derived organoids, and patient-derived xenografts.&lt;h3&gt;Results&lt;/h3&gt;In both proteomic- and transcriptomic-based subtyping analyses, subtypes characterized by hyperproliferative features demonstrated the poorest prognosis and the highest levels of RS. Among all first-line chemotherapeutic agents in these analyses, oxaliplatin accumulated the highest RS levels in HCC, while resistance remained a major challenge. With unbiased Kinome CRISPR loss-of-function gene screening, WEE1 was identified as a synthetic lethal target of oxaliplatin. The synergy between the WEE1 inhibitor adavosertib and oxaliplatin has been demonstrated in multiple in vitro and in vivo models. Mechanistically, adavosertib inhibits oxaliplatin-induced homologous recombination repair and G2/M checkpoint activation, leading to the accumulation of lethal DNA damage. Furthermore, patients with HCC showing high RS levels had poor prognoses and responded well to adavosertib and oxaliplatin combination treatments. This was validated by preclinical models and unsupervised clustering analysis.&lt;h3&gt;Conclusions&lt;/h3&gt;Our findings provide promising insights into the precise therapeutic targeting of RS in HCC at both the proteomic and transcriptomic levels. Furthermore, our study highlights the potential of combining oxaliplatin with adavosertib as a treatment approach for HCC.In this study, we analyzed 178 and 94 pairs of clinical HCC samples using proteomic and transcriptomic sequencing, respectively. We discovered that the subtype characterized by high proliferation had the worst prognosis and highest RS level. Drug screening revealed that oxaliplatin promotes RS accumulation in HCC, but its resistance remains a challenge. Through unbiased CRISPR deletion-gene screening, WEE1 was identified as a lethal target of oxaliplatin. The WEE1 inhibitor adavosertib inhibits oxaliplatin-induced DNA repair, leading to lethal DNA damage accumulation. Furthermore, our clustering analysis based on RS levels demonstrated that HCC patients with high RS levels have poorer prognoses and be more beneficial from adavosertib and oxaliplatin combination therapy. These findings support an ind","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"17 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451829","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":"NAC transcription factor GbNTL9 modifies the accumulation and organization of cellulose microfibrils to enhance cotton fiber strength","authors":"Mi Wu, Zhiyong Xu, Chao Fu, Nian Wang, Ruiting Zhang, Yu Le, Meilin Chen, Ningyu Yang, Yuanxue Li, Xianlong Zhang, Ximei Li, Zhongxu Lin","doi":"10.1016/j.jare.2025.02.022","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.022","url":null,"abstract":"<h3>Introduction</h3>Fiber strength is a critical determinant of fiber quality, with stronger fibers being highly preferred in the cotton textile industry. However, the genetic basis and the specific regulatory mechanism underlying the formation of cotton fiber strength remain largely unknown.<h3>Objectives</h3>To explore fiber strength-related genes, QTL mapping, map-based cloning, and gene function verification were conducted in a backcross inbred line BS41 derived from interspecific hybridization between upland cotton and sea-island cotton.<h3>Methods</h3>Upland cotton Emian22 (E22) and an interspecific backcross inbred line (BIL) BS41 were used as parents to construct secondary segregation populations for BSA and QTL mapping of fiber strength. The candidate gene <em>GbNTL9</em> was identified through map-based cloning and expression analysis. The function of <em>NTL9</em> was determined through transgenic experiments and cytological observations. The regulatory mechanisms of <em>NTL9</em> were explored using RNA-seq, RT-qPCR, yeast two-hybrid, bimolecular fluorescence complementation, and yeast one-hybrid.<h3>Results</h3>A major QTL for fiber strength, <em>qFS-A11-1</em>, was mapped to a 14.6-kb genomic region using segregating populations from E22 × BS41. <em>GbNTL9</em>, which encodes a NAC transcription factor, was identified as the candidate gene. Overexpression of both upland cotton genotype <em>NTL9</em>^E22 and sea-island genotype <em>NTL9</em>^BS41 in upland cotton enhanced fiber strength by facilitating the dense accumulation and orderly organization of cellulose microfibrils within the cell wall. Transcriptomic analysis revealed that <em>NTL9</em> inhibited the expression of genes involved in secondary wall synthesis, such as <em>CESA4</em>, <em>CESA7</em>, and <em>CESA8</em>, thereby delaying cell wall cellulose deposition and altering the microfibril deposition pattern. NTL9 interacted with MYB6 and functioned as a downstream gene in the ethylene signaling pathway. Additionally, an effective gene marker NTL9-24 was developed to distinguish haplotypes from <em>G. barbadense</em> and <em>G. hirsutum</em> for fiber quality breeding program.<h3>Conclusion</h3>Our findings demonstrate that <em>GbNTL9</em> positively regulates fiber strength through altering the microfibril deposition pattern, and provide a new insight into the molecular mechanism underlying fiber strength.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435792","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}