Journal of advanced research最新文献

{"title":"Low-dose PFNA exposure exacerbates intestinal inflammation via caspase-11-dependent noncanonical NLRP3 inflammasome activation in macrophages.","authors":"Kean Lu, Zhenyan Cui, Xiaohong Fei, Jiahe Zhang, Shusen Fang, Yuwei Wang, Yaxia Chen, Yihua Wu, Dajing Xia","doi":"10.1016/j.jare.2026.09.005","DOIUrl":"https://doi.org/10.1016/j.jare.2026.09.005","url":null,"abstract":"<p><strong>Introduction: </strong>Per- and polyfluoroalkyl substances (PFASs) have been implicated in promoting the progression of intestinal inflammation. However, the specific mechanisms remain unclear.</p><p><strong>Objectives: </strong>This study aimed to elucidate how PFASs exacerbate inflammatory bowel disease (IBD) progression by directly influencing macrophages, investigate the underlying molecular mechanisms, and explore potential interventions.</p><p><strong>Methods: </strong>Primary mouse peritoneal macrophages (PMs) and a chronic colitis model were utilized to investigate the impacts of three typical PFASs, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), on the progression of IBD to clarify the underlying mechanisms and potential interventions.</p><p><strong>Results: </strong>Our study found that PFNA induced significant proinflammatory responses, characterized by marked upregulation of IL-1β and IL-18 under environmentally relevant concentrations. Mechanistically, PFNA activated the caspase-11-dependent noncanonical NLRP3 inflammasome, thereby inducing dose-dependent upregulation of caspase-1, N-GSDMD, IL-1β, and IL-18. Both caspase-11 knockdown and Z-VAD-FMK inhibition attenuated these inflammatory effects. Molecular docking suggested that PFNA might induce NLRP3 inflammasome activation by interacting with pro-caspase-11. In vivo, PFNA also aggravated IBD progression through the same pathway. Conversely, based on our previous study, myricetin was found to alleviate PFNA-induced inflammation by inhibiting the caspase-11/NLRP3 axis.</p><p><strong>Conclusion: </strong>Our study reveals a molecular axis through which PFNA exacerbates intestinal inflammation and identifies myricetin as a potential intervention for IBD associated with PFNA exposure. These findings provide insights into the mechanisms of PFNA-induced intestinal toxicity and may guide the development of strategies to mitigate PFNA-associated intestinal inflammation.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148893123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clofoctol-derived amphiphilic peptidomimetics exhibit broadened antimicrobial activity via multiple contributing mechanisms.","authors":"Jiayong Liu, Jia-Hui Lin, Wenyi Wang, Hongxia Li, Jiahui Zhengyu, Yuyan Zhang, Mu Chen, Rongcui Zhong, Xing Chong, Yuanye Dang, Huili Chang, Shouping Liu, Shuimu Lin","doi":"10.1016/j.jare.2026.09.007","DOIUrl":"https://doi.org/10.1016/j.jare.2026.09.007","url":null,"abstract":"<p><strong>Introduction: </strong>Antimicrobial resistance (AMR) poses an escalating global health threat, yet the antibiotic discovery pipeline has stagnated over recent decades. Multi-mechanistic antibacterial action may offer a promising strategy to address this challenge.</p><p><strong>Objectives: </strong>This study aimed to use clofoctol, a clinically used antibacterial agent, as the starting scaffold for cationic amphiphilic modification to generate derivatives with improved aqueous solubility, broadened antibacterial spectrum, and enhanced selectivity, followed by mechanistic characterization of the lead compound.</p><p><strong>Methods: </strong>Minimum inhibitory concentration (MIC) and hemolysis assays were performed to assess structure-activity relationship of clofoctol derivatives. The lead compound was then systematically evaluated for bactericidal kinetics, resistance development, antibiofilm activity, salt tolerance, mammalian cytotoxicity, and therapeutic efficacy in a murine keratitis model. To investigate the mechanisms, we evaluated membrane perturbation, topoisomerase IV-mediated DNA decatenation, intracellular reactive oxygen species (ROS) and adenosine triphosphate (ATP) quantification, transcriptomic analysis, and RT-qPCR validation.</p><p><strong>Results: </strong>30 was identified as the lead candidate, displaying improved apparent aqueous solubility, broadened activity against Gram-positive and Gram-negative bacteria (MICs = 0.39-3.125 µg/mL), favorable selectivity index and therapeutic index (TI = 272.5) relative to clofoctol. Furthermore, 30 exhibited rapid bactericidal kinetics, good salt tolerance, and low propensity for resistance development. In a murine keratitis model, 30 reduced bacterial burden by 4.65 and 3.81 log CFU in S. aureus ATCC29213- and P. aeruginosa ATCC9027- induced infections, respectively. These reductions were comparable to those achieved by vancomycin and gatifloxacin under the same conditions, and no observable ocular toxicity was detected. Mechanistic investigation supported membrane perturbation as the best-supported antibacterial component. Compound 30 exposure was also associated with intracellular ATP depletion, ROS accumulation, and in vitro inhibition of topoisomerase IV-mediated DNA decatenation.</p><p><strong>Conclusion: </strong>These results identify 30 as a promising antimicrobial agent with broadened antibacterial activity, favorable preliminary safety profiles, and multiple contributing antibacterial mechanisms.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148893187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Nrf2 in oxidative liver injury: expanding the role of gut microbiota and metabolites.","authors":"Yusha Luo, Yican Jiang, Zhou Tingting","doi":"10.1016/j.jare.2026.09.006","DOIUrl":"https://doi.org/10.1016/j.jare.2026.09.006","url":null,"abstract":"<p><strong>Background: </strong>Liver diseases are a major cause of illness and death worldwide. Oxidative stress is a pivotal driver in the pathogenesis of a spectrum of liver diseases, including alcoholic liver disease (ALD), metabolic dysfunction-associated fatty liver disease (MAFLD), drug-induced liver injury (DILI), and hepatocellular carcinoma (HCC). The transcription factor Nrf2, a master regulator of cellular antioxidant responses, plays a central yet context-dependent role in modulating this injury. Additionally, the gut-liver axis is a critical regulator of hepatic homeostasis.</p><p><strong>Aim of review: </strong>This review presents recent advances to propose a refined gut-microbiota-Nrf2 axis as a key mechanistic link in the treatment of liver injury. We detail how specific gut-derived microbial metabolites, such as short-chain fatty acids (SCFAs), tryptophan derivatives, and urolithins, directly or indirectly activate the hepatic Keap1/Nrf2 signaling pathway. This activation orchestrates a cytoprotective program that enhances the redox balance, promotes detoxification, and induces selective autophagy, thereby protecting against oxidative liver injury. Conversely, we examine the dual role of Nrf2, highlighting how its dysregulated and constitutive activation in established HCC can paradoxically promote tumor progression and ferroptosis resistance. Finally, we evaluate the therapeutic potential of targeting this axis using microbiome-modulating strategies, including probiotic and prebiotic supplementation, fecal microbiota transplantation (FMT), dietary intervention, and synergy with Nrf2-targeting drugs.</p><p><strong>Key scientific concepts of review: </strong>This review provides an integrated framework that connects gut microbial ecology with host redox signaling, offering novel mechanistic insights and translational perspectives for the prevention and treatment of oxidative liver diseases.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148893138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PHGDH-derived serine is essential for vascular remodeling after stroke.","authors":"Zhongwang Liu, Chenxi Liu, Pengyue Du, Xue Geng, Shaochen Wang, Zihan Wang, Yu Huang, Luping Chang, Yong-Chen Wang, Wenying Fan, Bing-Qiao Zhao","doi":"10.1016/j.jare.2026.09.004","DOIUrl":"https://doi.org/10.1016/j.jare.2026.09.004","url":null,"abstract":"<p><strong>Introduction: </strong>Astrocytic-vascular crosstalk contributes to vascular repair and remodeling after brain injury. 3‑Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting serine synthetic enzyme, has emerged as a crucial factor in cell growth and metabolism. However, the role of PHGDH in ischemic stroke is poorly understood.</p><p><strong>Objectives: </strong>This study aimed to determine whether PHGDH-derived serine contributes to neovascularization and functional recovery after ischemic stroke.</p><p><strong>Methods: </strong>We employed astrocyte-specific PHGDH deletion and PHGDH overexpressing mice to evaluate the role of PHGDH in poststroke neovascularization, vascular remodeling and functional recovery. To explore the interaction between vascular solute carrier family 38 member 2 (SLC38A2) and astrocytic PHGDH, we knocked down SLC38A2 in PHGDH-overexpressing mice using an AAV-BR1 carrying shRNA (shSlc38a2) virus. Moreover, we treated mice with mammalian target of rapamycin complex1 (mTORC1) inhibitor rapamycin to assess the effect of mTORC1 on angiogenesis and vascular integrity after ischemic stroke.</p><p><strong>Results: </strong>The expression of PHGDH was significantly upregulated in astrocytes during stroke recovery, which led to the accumulation of serine in the ischemic cortex. Deletion of PHGDH in astrocytes decreased the amount of serine and enhanced vascular permeability, impaired neovascularization and the formation of functional vessels, and decreased vascular perfusion and cerebral blood flow at 14 days after ischemic stroke. In contrast, overexpression of astrocytic PHGDH increased serine levels, promoted neovascularization and vascular remodeling, and improved blood flow and long-term functional recovery. These effects were mediated through the SLC38A2 transporter, and endothelial silencing of SLC38A2 resulted in decreased vascular serine levels and the inactivation of mTORC1, and blocked neovascularization and vascular repair in PHGDH-overexpressing mice. Moreover, infusion of rapamycin impaired vascular repair and plasticity.</p><p><strong>Conclusion: </strong>Our observations demonstrate that poststroke neovascularization is regulated by astrocytic-vascular interaction involving PHGDH-mediated elevation of serine.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148893175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of a novel high-capacity dry plasma biosampling-lateral flow device for the testing of traumatic brain injury protein biomarkers.","authors":"Firas Kobeissy, Eman Elbayoumi, Rawad Daniel Arja, Guangzheng Cai, Khadija Boukholda, Seza Apiliogullari, Michele D Nelson, Hamad Yadikar, Ali Mostafa Alawieh, Jonathan A Grossberg, Yehia Mechref, Amy K Wagner, Richard Rubenstein, Claudia Robertson, Jose-Miguel Yamal, Spyridoula Tsetsou, Raquel C Gardner, Kevin K Wang","doi":"10.1016/j.jare.2026.09.003","DOIUrl":"https://doi.org/10.1016/j.jare.2026.09.003","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background and purpose: &lt;/strong&gt;Current blood-based diagnostic tests for traumatic brain injury (TBI), such as those measuring UCH-L1 and GFAP, require venous whole blood or plasma samples collection and cold-chain handling. No FDA-cleared TBI test currently supports capillary blood or dried sample formats. We propose incorporating a novel dried plasma collection device into future TBI diagnostic workflows. This format is compatible with fingerstick sampling, simplifies storage and transport, reduces biosampling burdens, and preserves key TBI biomarker detectability. Our study evaluates this device's analytical performance, focusing on biomarker stability under various storage conditions and its compatibility with multiplex TBI biomarker assays.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Capillary blood (50-70 µL) or archived plasma was applied to a Dried Plasma Biosampling Lateral Flow (DPB-LF) device. The device separates plasma via a cell filter onto a nitrocellulose strip. After air-drying for 30 min, samples were stored with desiccants under various temperatures and durations. Later, dried plasma was rehydrated and analyzed using the Quanterix Neurology 4-Plex B assay, and biomarker levels were compared to matched wet plasma samples.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;With capillary blood from healthy controls, the DPB-LF device demonstrated consistent plasma separation. SDS-PAGE analysis showed similar protein profiles in dried versus wet plasma. As proof of principle, pooled plasma samples from TBI patients and healthy controls were applied to DPB-LF devices and stored at different temperatures (4 °C, room temperature, and 40 °C) and durations (1, 7, 14, and 21 days). Upon rehydration, dried TBI plasma samples consistently yield robust recovery of GFAP, UCH-L1, NfL, and Tau signals at 4 °C across all time points and at room temperature for up to 7 days. Extended storage durations and elevated temperatures (14-21 days at room temperature, or 7-21 days at 40 °C) led to partial reductions in biomarker signal recovery, as expected. Additionally, archived plasma samples from 16 geriatric TBI patients (GCS 13-15) were applied to the DPB-LF device. Upon rehydration, biomarker levels from the dried samples showed strong correlations with matched wet plasma, with R&lt;sup&gt;2&lt;/sup&gt; ranging from 0.829 to 0.995 for GFAP, NfL, Tau, and UCH-L1. We further examined the DPB-LF device using plasma samples from a second independent cohort of 44 adult TBI subjects (GCS 3-15) collected on post-injury day 1. Dried plasma demonstrated robust prediction of cranial lesions on computed tomography, with AUC/ROC values of 0.756, 0.734, 0.738, and 0.703 for GFAP, NfL, Tau, and UCH-L1, respectively. All four biomarker levels measured in dried plasma also showed significant correlations with injury severity categories (GCS 3-8, 9-12, and 13-15) using nonparametric Kruskal-Wallis testing.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;The DPB-LF device enables minimally invasive capillar","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148893121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mulberry-derived endophytic Bacillus velezensis suppresses gray mold and promotes mulberry growth via reshaping the root metabolism and microbiome.","authors":"Lixue Wang, Yixuan Zhang, Wanting Li, Xinyi Zhang, Cheng Li, Yinxin Liu, Zhenzhu Su, Yue Wang, Chongde Sun, Lingxia Huang","doi":"10.1016/j.jare.2026.09.002","DOIUrl":"https://doi.org/10.1016/j.jare.2026.09.002","url":null,"abstract":"<p><strong>Introduction: </strong>Gray mold is an important fungal disease caused by Botrytis cinerea which threatens global agriculture. As chemical control faces limitations, biological control using Bacillus has gained attention for its environmental friendliness and growth promotion. However, their ecological basis and application potential in mulberry gray mold control remain insufficiently understood.</p><p><strong>Objective: </strong>This study aimed to evaluate the biocontrol efficacy of the mulberry derived endophytic strain Bacillus velezensis ZJU_268 and to investigate its associated effects on plant growth, root-associated microbiomes, and metabolic profiles.</p><p><strong>Methods: </strong>Greenhouse assays were combined with genomic and comparative genomic analyses, amplicon sequencing, non-targeted metabolomics, and functional validation of isolated microbes and metabolites to assess the effects of ZJU_268 and its cell free supernatant (CFS) on mulberry seedlings.</p><p><strong>Results: </strong>This study isolated a mulberry derived endophytic bacterium, B. velezensis ZJU_268, which exhibits strong antifungal activity and reduces the incidence of gray mold in mulberry seedlings. Whole-genome sequencing and comparative genomic analyses revealed strain-specific regions and genes associated with root colonization, stress adaptation, and antimicrobial biosynthesis. Both live cells and CFS significantly promoted seed germination, seedling growth, and biomass accumulation in a dose dependent manner. Amplicon sequencing showed that ZJU_268 and its supernatant reshaped the mulberry root microbiome, enriching beneficial bacterial and fungal taxa while reducing potentially pathogenic members. Cultivable members of the enriched microbiota displayed strong antifungal activity against B. cinerea and promoted mulberry growth. Metabolomic profiling further showed that ZJU_268 and its supernatant were associated with marked metabolic shifts in mulberry roots, accompanied by the accumulation of selected metabolites that supported the growth of representative enriched isolates.</p><p><strong>Conclusions: </strong>This study demonstrates that ZJU_268 suppresses gray mold and promotes mulberry growth in association with direct antagonistic activity, microbiome restructuring, and holobiont-level metabolic shifts, providing a promising biological strategy for sustainable mulberry disease management.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomimicry TRPV1 agonist 6SA attenuates corticosterone-induced depression via targeting Glul-Gm57375 signaling in microglia.","authors":"Yilu Sun, Weiyao Liao, Stephen Cho Wing Sze, Yibin Feng, Jianhui Rong, Jia Zhao","doi":"10.1016/j.jare.2026.09.001","DOIUrl":"https://doi.org/10.1016/j.jare.2026.09.001","url":null,"abstract":"<p><strong>Introduction: </strong>Microglia-mediated neuroinflammation hallmarks the pathophysiology of depression. We recently identified 6-shogaol (6Sh) from the ginger root (Rhizoma Zingiberis Recens) as a potent anti-neuroinflammatory and antidepressant drug candidate.</p><p><strong>Objectives: </strong>This study aimed to resolve the bioavailability and cost-effectiveness of 6Sh for the development of novel anti-neuroinflammatory drugs against depression.</p><p><strong>Methods: </strong>A biomimicry 6Sh analog (6SA) with an amide moeity is chemically synthesized by directly coupling vanillylamine with trans-2-octenoic acid and pharmacologically evaluated in a mouse model of corticosterone-induced depression. Single-cell RNA sequencing (scRNA-Seq) was performed to profile the brain spatial transcriptomic responses to 6SA for molecular insights to define the antidepressant mechanisms.</p><p><strong>Results: </strong>As results, 6SA outperforms the parent 6Sh in terms of water solubility, oral bioavailability, cytotoxicity, cost-effectiveness and pharmacokinetic profile. Remarkably, 6SA more effectively attenuated neuroinflammation and depressive-like behaviors while demonstrated good safety profile in mice. Mechanistically, the scRNA-Seq results highlighted two important differentially expressed genes (i.e., Glul and lncRNA Gm57375) in the prefrontal cortex microglia. Strikingly, in vivo and in vitro experiments indicated that 6SA regulated Glul and Gm57375 expression in a TRPV1-dependent manner.</p><p><strong>Conclusion: </strong>Thus, 6SA may be a promising drug candidate with the capacity to tune neuroinflammation via targeting the TRPV1-Glul-Gm57375 axis in microglia against depression.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methionine γ-lyase traps cofactor pyridoxal-5'-phosphate through specific serine-mediated affinity.","authors":"Xueting Liu, Chang Yan, Ruiqi Su, Mengwen Shi, Zhi Geng, Ying Chen, Liwen Zhu, Zongjie Dai, Junfeng Hui, Xi Chen, Kai-Zhi Jia","doi":"10.1016/j.jare.2026.08.062","DOIUrl":"10.1016/j.jare.2026.08.062","url":null,"abstract":"<p><strong>Introduction: </strong>Pyridoxal-5'-phosphate (PLP), the ubiquitous and ancient cofactor, plays important roles in enzymatic elimination, transamination and other reactions. The catalytic efficiency of PLP-dependent enzymes is significantly higher than that of free PLP. The recruitment of solution PLP by the enzymes, particularly through interactions outside the active-site entrance, is the key step determining the occurrence of PLP-mediated catalysis. However, the precise mechanism by which enzymes recruit solution PLP remains elusive.</p><p><strong>Objectives: </strong>This study aims to elucidate the mechanism by which enzymes, specifically methionine γ-lyase (MGL) that suppresses cancer cell proliferation through serum or dietary methionine depletion, recruit solution PLP and to investigate the role of the C-terminal domain in this process. The study also seeks to explore the relationship between PLP recruitment and the efficient L-methionine catabolism in the host organism.</p><p><strong>Methods: </strong>We report the crystal structure of yMGL, which belongs to a newly identified subgroup of cystathionine γ-lyases, in complex with L-methionine and PLP. To investigate the functional role of the C-terminal domain in PLP recruitment and enzyme activity, we performed C-terminal domain truncations and mutations and assessed their effects both in vitro and in vivo, analyzing changes in PLP binding affinity and L-methionine catabolism, respectively.</p><p><strong>Results: </strong>Through structural, biochemical, bioinformatic and metabolic analyses, we demonstrate that the C-terminal domain of yMGL, outside the canonical PLP-binding domain, is essential for the specific interaction between yMGL and PLP, and L-methionine catabolism. A conserved Ser residue within this domain, located outside of active-site entrance, determines PLP recruitment.</p><p><strong>Conclusion: </strong>These findings elucidate a previously uncharacterized mechanism of PLP recruitment by MGLs and enable rational design of MGLs with enhanced PLP binding and catalytic performance.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148868609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Driver genomic lesions in MDM2, CDK4, and JUN co-opt targetable super-enhancer networks to impose liposarcomagenic core regulatory circuitry.","authors":"Ye Chen, Ying Zhang, Long Xie, Xiaorui Fan, Jiyang Liu, Tuan Zea Tan, Zhengming Yang, Pushkar Dakle, Suya Zheng, Nan Li, Chenying Wang, Victor Kwanmin Lee, Lingwen Ding, Qiaoyang Sun, Wen Yi, H Phillip Koeffler, Liang Xu","doi":"10.1016/j.jare.2026.08.055","DOIUrl":"10.1016/j.jare.2026.08.055","url":null,"abstract":"<p><strong>Introduction: </strong>Amplification of chromosome 12q13-15 spanning MDM2 and CDK4 genes serves as a molecular diagnostic hallmark of dedifferentiated liposarcoma (DDLPS), an aggressive soft-tissue sarcoma. Epigenetic activation of master transcription factors (RUNX proteins, FOSL2, and MYC) establishes a self-reinforcing oncogenic transcriptional circuitry in DDLPS. Nevertheless, the collaborative interplay between genomic alterations and epigenetic dysregulation in defining DDLPS cell identity remains elusive.</p><p><strong>Objectives: </strong>This work aimed to elucidate the primary genetic drivers and mechanistic basis of DDLPS-specific core transcriptional regulatory circuitry.</p><p><strong>Methods: </strong>We performed integrative chromatin profiling analysis of DDLPS clinical specimens and cell lines to map cis-regulatory landscapes. Cistromes of MDM2, JUN, and E2F1 were delineated through chromatin immunoprecipitation sequencing in two DDLPS models. Essential driver functions and transcriptional regulatory effects of key regulators were assessed via various genetic manipulation approaches. Synergistic interactions between BET-targeting agents and MDM2/p53 or CDK4 inhibitors were quantified by cell viability assays. In vivo xenograft assays evaluated the oncogenic potential of key regulators and the therapeutic efficacy of novel strategies.</p><p><strong>Results: </strong>Co-amplification of MDM2, CDK4, and JUN during sarcomagenesis converges with BET protein-dependent chromatin remodeling to fuel feed-forward transcriptional circuits among master transcription factors. Mechanistically, excessively expressed MDM2 stabilizes the core regulatory circuitry by forming chromatin-bound complexes with JUN/FOSL2 at cis-regulatory elements, especially super-enhancers across DDLPS genome. Concurrently, CDK4 maintains expression of E2F1 which further fosters transcriptional output of master transcription factors in DDLPS cells. Leveraging DDLPS-selective overexpression of MDM2 and its E3 ligase activity, targeted degradation of BET proteins by MDM2-recruiting proteolysis targeting chimera selectively disrupted the core regulatory circuitry, suppressing DDLPS growth and exhibiting strong synergy with CDK4 inhibitor.</p><p><strong>Conclusion: </strong>DDLPS-associated genomic lesions collaborate with BET-dependent chromatin regulation to establish disease-sustaining transcriptional circuitry. Our findings also provide a mechanistic rationale for harnessing MDM2's E3 ligase activity to therapeutically degrade oncoproteins in MDM2-amplified malignancies.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148868577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Steering biofortification of Zn, Fe and Se in staple cereals (wheat, maize and rice) for micronutrient hunger mitigation: from trials to industrialized food products.","authors":"Haiyong Xia, Hao Yang, Liping Ma, Licheng Song, Peiguo Zhao, Daiyin Chao, Xiaoba Wu, Chunming Liu, Caixian Tang, Fang-Jie Zhao","doi":"10.1016/j.jare.2026.08.061","DOIUrl":"10.1016/j.jare.2026.08.061","url":null,"abstract":"<p><strong>Background: </strong>\"Hidden hunger\" caused by zinc (Zn), iron (Fe), and selenium (Se) deficiencies remains a major global health challenge, especially for populations relying on cereal-based diets in developing countries. While conventional food fortification and dietary supplementation work, biofortification of staple cereals (wheat, maize, and rice) through agronomic practices and breeding/biotechnological approaches offers a sustainable, food-based solution with long-term impact. However, existing literature has two key gaps. (1) Fragmented analysis: a lack of systematic cross-nutrient, cross-crop analysis of Zn/Fe/Se biofortification feasibility across wheat, maize, and rice. (2) Disconnection from industry: insufficient integration of agronomic and breeding/biotechnological technologies with food processing, market demand, and consumer health outcomes-failing to scale up trial results into industrialized products.</p><p><strong>Aim of review: </strong>This review seeks to address the aforementioned knowledge gaps and outline a conceptual framework to help bridge the \"trial-to-industry\" divide in Zn/Fe/Se biofortification of staple cereals, aiming to support researchers, policymakers, and food enterprises in joint efforts to mitigate global micronutrient malnutrition and advance the United Nations 2030 \"Zero Hunger\" Goal.</p><p><strong>Key scientific concepts of review: </strong>The biofortification feasibility (levels of difficulty, similarities, and differences) of Zn, Fe, and Se in wheat, maize, and rice was systematically compared. It is easier to biofortify Se than Zn and Fe. Recent agronomic innovations, including drone-based foliar spraying, nanofertilizers, and integrated soil-crop system management, show significant promise for scalable biofortification. To develop consumer-acceptable micronutrient-enriched functional agri-food products complying with nutrition labeling and health claim regulations, several critical advances are needed: improved translocation and biosynthesis of Zn/Fe-nitrogen/protein complexes into the endosperm, advanced Zn/Fe-preserving \"whole-ingredient\" processing and selenomethionine extraction, and strengthened clinical evidence, policy frameworks and market guidance (particularly for Se safety). Finally, this review outlines a staged, comprehensive roadmap for integrating innovation across the industrial chain and clarifies the industrialization progress and technical maturity of each micronutrient.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148860681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}