Journal of Advanced Research最新文献

{"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}

{"title":"Autoimmune responses to myelin-associated proteins as diagnostic and prognostic biomarkers of relapsing-remitting multiple sclerosis: Associations with human herpesvirus-6 and Epstein-Barr virus reactivation","authors":"Aristo Vojdani, Abbas F. Almulla, Elroy Vojdani, Jing Li, Yingqian Zhang, Michael Maes","doi":"10.1016/j.jare.2025.02.021","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.021","url":null,"abstract":"<h3>Background</h3>The pathogenesis of relapsing-remitting multiple sclerosis (RRMS) is linked to autoimmune attacks against myelin proteins, and reactivation of Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6). However, the connection between viral reactivation and autoimmune biomarkers has remained unclear.<h3>Objectives</h3>To investigate immunoglobulin (Ig)G/IgA/IgM responses targeting myelin-related proteins in association with EBV and HHV-6 replication markers in RRMS.<h3>Methods</h3>We recruited 55 patients with RRMS and 63 healthy controls and assessed IgG/IgA/IgM responses against seven myelin-related components, as well as EBV nuclear antigen 1 (EBNA-1) and deoxyuridine-triphosphate nucleotidohydrolase (dUTPases). Disability was evaluated using the Expanded Disability Status Scale (EDSS) and disease progression using the Multiple Sclerosis Severity Score (MSSS).<h3>Results</h3>IgG/IgA/IgM levels targeting seven myelin-related proteins were significantly higher in RRMS than in controls. IgG against myelin basic protein (MBP) (IgG-MBP), IgM-myelin-associated glycoprotein (IgM-MAG)-37–60, IgA-MBP, and IgA-myelin-oligodendrocyte-glycoprotein (IgA-MOG-31–55) distinguished RRMS from controls with a predictive accuracy of 96.6 % (sensitivity = 95.7 %, specificity = 95.2 %) and an area under the ROC curve of 0.991. A large part of the variance in the EDSS (around 75 %) and MSSS score (62.8 %) was explained by IgG-MBP, IgM-MBP, IgA-MOG-31–55, and IgM-MAG. Part of the variance (47.4 %) in the IgG/IgA/IgM responses to myelin-related proteins was explained by immune responses to EBNA and dUTPases of EBV and HHV-6.<h3>Conclusions</h3>Autoimmune reactivities targeting myelin-related proteins are valuable biomarkers of RRMS and the severity and progression of RRMS. Reactivation of EBV and HHV-6 may trigger or maintain these autoimmune responses thereby impacting disease progression.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"21 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427342","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":"H4K12 lactylation potentiates mitochondrial oxidative stress via the Foxo1 pathway in diabetes-induced cognitive impairment","authors":"Ying Yang, Lulu Song, Liping Yu, Jinping Zhang, Bo Zhang","doi":"10.1016/j.jare.2025.02.020","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.020","url":null,"abstract":"<h3>Aims</h3>To investigate the role and potential mechanisms of H4K12 lactylation modifications in diabetes-related cognitive impairment (DACD).<h3>Methods</h3>Behavioral tests, HE staining, and immunohistochemistry were employed to assess cognitive function and the extent of brain tissue injury. Metabolomics and proteomics were applied to profile the metabolic regulatory network. We measured lactic acid and Pan-Kla levels in the brains of T2DM mice and high glucose-treated microglia. CUT&amp;Tag technology was utilized to identify genes regulated by H4K12la. Small interfering RNA (siRNA) sequences and adeno-associated viruses (AAVs) were used to knock down key components in signaling pathways, evaluating the impact of histone lactylation on microglial polarization.<h3>Results</h3>Lactic acid levels were significantly higher in the brains of T2DM mice and high glucose-treated microglia compared to controls, leading to an increase in pan histone lysine lactylation (Kla). We found that lactate directly induced an increase in H4K12la. CUT&amp;Tag analysis revealed that elevated H4K12la activates the FOXO1/PGC-1α signaling pathway by enhancing binding to the FOXO1 promoter, promoting mitochondrial oxidative stress.<h3>Conclusion</h3>This study demonstrated that elevated H4K12la directly activates the FOXO1 signaling pathway, promoting oxidative stress and contributing to DACD phenotypes.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"136 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427341","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 single-cell analysis deciphered the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury","authors":"Juan Li, Mengjuan Xuan, Li Yang, Yingru Liu, Na Lou, Leiya Fu, Qingmiao Shi, Chen Xue","doi":"10.1016/j.jare.2025.02.018","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.018","url":null,"abstract":"<h3>Introduction</h3>Sepsis-related acute liver injury involves complex immune dysfunctions. Epoxyeicosatrienoic acids (EETs), bioactive molecules derived from arachidonic acid (AA) via cytochrome P450 (CYP450) and rapidly hydrolyzed by soluble epoxide hydrolase (sEH), possess anti-inflammatory properties. Nevertheless, the impact of the sEH inhibitor TPPU on sepsis-related acute liver injury remains uncertain.<h3>Objectives</h3>This study utilized comprehensive single-cell analysis to investigate the immunoregulatory mechanism of TPPU in alleviating sepsis-related acute liver injury.<h3>Methods</h3>Hepatic bulk RNA sequencing and proteomics analyses were employed to investigate the mechanisms underlying sepsis-related acute liver injury induced by cecal ligation and puncture in mice. Cytometry by time-of-flight and single-cell RNA sequencing were conducted to thoroughly examine the immunoregulatory role of TPPU at single-cell resolution.<h3>Results</h3>Downregulation of AA metabolism and the CYP450 pathway was observed during sepsis-related acute liver injury, and TPPU treatment reduced inflammatory cytokine production and mitigated sepsis-related hepatic inflammatory injury. Comprehensive single-cell analysis revealed that TPPU promotes the expansion of anti-inflammatory CD206⁺CD73⁺ M2-like macrophages and PDL1^-CD39^-CCR2⁺ neutrophils, reprogramming liver neutrophils to an anti-inflammatory CAMP⁺NGP⁺CD177⁺ phenotype. Additionally, TPPU inhibits the CCL6-CCR1 signaling mediated by M2-like macrophages and CAMP⁺NGP⁺CD177⁺ neutrophils, altering intercellular communication within the septic liver immune microenvironment.<h3>Conclusion</h3>This study demonstrated TPPU’s protective efficacy against sepsis-related acute liver injury, underscoring its vital role in modulating liver macrophages and neutrophils and enhancing prospects for personalized immunomodulatory therapy.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"24 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418165","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":"Specific Macronutrient clusters associated with lower mortality Risk: Evidence from NHANES 1999–2018","authors":"Jiaying Yu, Yang Chen, Defang Li, Lan Zhang, Yuting Zhang, Jiaqi Zhang, Jiayu Zhu, Zican Li, Hongxin Fu, Dongwei Guan, Runan Zhang, Liyan Liu, Cheng Wang, Changhao Sun, Rennan Feng","doi":"10.1016/j.jare.2025.02.019","DOIUrl":"https://doi.org/10.1016/j.jare.2025.02.019","url":null,"abstract":"<h3>Introduction</h3>Accumulating evidence suggest that imbalanced macronutrient composition would increase the risk of chronic diseases. However, previous studies that predominantly focused on individual macronutrients often failed to thoroughly elucidate this complex association.<h3>Objectives</h3>This study aimed to comprehensively analyze the relationship between macronutrient clusters and all-cause mortality.<h3>Methods</h3>The study included 26,615 adults aged 20–75 years from the National Health and Nutrition Examination Survey (NHANES) 1999–2018. A three-dimensional cube method was employed to categorize clusters of macronutrients intake. The association between dietary macronutrient clusters and all-cause mortality was investigated using Cox proportional hazards modeling and restricted cubic spline (RCS) analysis.<h3>Results</h3>Over a weighted median follow-up duration of 7.58 years, 3,998 deaths were recorded. After adjusting for potential confounders, compared with the reference Cluster _Pm:Fm:Cmh, 4 specific Clusters were associated with reduced all-cause mortality: Cluster _Pm:Fm:Cm (HR: 0.79, 95 % CI: 0.67–0.92), Cluster _Pm:Fmh:Cml (HR: 0.76, 95 % CI: 0.61–0.95), Cluster _Pm:Fmh:Cm (HR: 0.86, 95 % CI: 0.75–0.97), and Cluster _Pl:Fm:Cmh (HR: 0.73, 95 % CI: 0.60–0.89). Three-node RCS analysis revealed non-linear relationships between carbohydrate within Cluster _Pm:Fm:Cm and protein within Cluster _Pl:Fm:Cmh and overall mortality. Subgroup and sensitivity analyses corroborated the robustness of these associations across different age, gender, and energy intake levels.<h3>Conclusions</h3>This study employed a three-dimensional cube approach to categorize the human macronutrients intake into 24 clusters. Cluster _Pm:Fm:Cm, Clusters _Pm:Fmh:Cml, Cluster _Pm:Fmh:Cm, and Cluster _Pl:Fm:Cmh exhibited a lower mortality risk. Different clusters of macronutrients could be a precondition in nutrition intervene strategy.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"24 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418203","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}