Journal of Advanced Research最新文献

{"title":"Fe-S cluster deficiency drives small colony variant formation in persistent infections","authors":"Tianchi Chen, Zhiyi Ye, Weiyi Huang, Qi Zhang, Feng Jiang, Ziyu Yang, Ying Jian, Yanan Wang, Guoxiu Xiang, Qian Liu, Hao Shen, Min Li, Lei He","doi":"10.1016/j.jare.2025.05.018","DOIUrl":"https://doi.org/10.1016/j.jare.2025.05.018","url":null,"abstract":"<h3>Introduction</h3>Small colony variants (SCVs) of <em>Staphylococcus aureus</em> (<em>S. aureus</em>) are associated with persistent infections and poor clinical outcomes. The mechanisms driving stable SCV formation remain poorly understood, particularly concerning metabolic adaptations. This study explores the in-host evolutionary dynamics of <em>S. aureus</em> and identifies a novel genetic determinant linked to SCV formation.<h3>Objectives</h3>To investigate the genetic mutations and phenotypic adaptations underlying SCV formation, with a focus on the role of a novel mutation in the <em>sufB</em> gene, which is critical for Fe-S cluster biosynthesis.<h3>Methods</h3>Sequential isolates from a patient with recurrent infections were analyzed using whole-genome sequencing, antimicrobial susceptibility testing, and functional assays. The phylogenetic relationship of the isolates was determined, and specific mutations were identified. Functional assays included aconitase and glutamate synthase activity measurements, ATP level quantification, reactive oxygen species (ROS) production, and biofilm formation assays. In vivo pathogenesis was assessed using a murine catheter infection model.<h3>Results</h3>A novel frameshift mutation in <em>sufB</em> was identified, disrupting Fe-S cluster biosynthesis and impairing the TCA cycle and electron transport chain, leading to reduced ATP and ROS production. This metabolic reprogramming promoted stable SCV formation, characterized by slow growth, enhanced tolerance to antibiotics and neutrophil-mediated killing, and persistent inflammation in vivo. Restoration of <em>sufB</em> reversed these phenotypes, confirming its pivotal role in SCV-associated persistence.<h3>Conclusion</h3><em>sufB</em> is a novel genetic determinant of stable SCV formation through Fe-S cluster deficiency, driving metabolic shifts that enhance immune evasion and chronic infection. Our findings highlight antibiotic stewardship and suggest potential therapeutic strategies for managing persistent SCV-associated infections.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"141 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979921","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":"Association between dietary amino acid intake and the risk of metabolic dysfunction-associated steatotic liver disease","authors":"Ruoqi Zhou, Xinrong Zhang, Xinxin Liu, Rui Huang, Yuwei Wang, Dajing Xia, Xue Li, Yihua Wu, Yu Shi","doi":"10.1016/j.jare.2025.05.029","DOIUrl":"https://doi.org/10.1016/j.jare.2025.05.029","url":null,"abstract":"<h3>Introduction</h3>Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is becoming the major chronic liver disease, and diet plays crucial role in MASLD prevention.<h3>Objectives</h3>The study aimed to explore the association between dietary amino acids with MASLD risk.<h3>Methods</h3>Utilizing data from the U.S. NHANES (2017–2020) and UK Biobank (2006–2010), we investigated the association between dietary intake of combined or specific amino acids, and the risk of MASLD, severe MASLD and MASLD-related events. And we identified MASLD-risk amino acid intake patterns and their primary food sources.<h3>Results</h3>The study included 5,568 participants from the U.S. NHANES and 48,261 from the UK Biobank, with MASLD prevalence of 34.3 % and 28.4 %, respectively. In QGC model, each quartile increase in combined amino acid intake was associated with a higher MASLD risk in the U.S. NHANES (aOR = 1.17, 95 % CI: 1.01–1.37, <em>P =</em> 0.035) and UK Biobank (aOR = 1.07, 95 % CI: 1.002–1.15, <em>P</em> = 0.042). Increased lysine intake was particularly linked to elevated MASLD risk in U.S. NHANES (aOR = 1.49, 95 % CI: 1.08–2.05, <em>P</em> = 0.023) and UK Biobank (aOR = 1.12, 95 % CI: 1.01–1.24, <em>P</em> = 0.032). Substituting lysine with other amino acids was associated with reduced MASLD risk. Lysine intake was also associated with a higher risk of severe MASLD (aHR = 1.13, 95 % CI: 1.04–1.23, <em>P =</em> 0.002) but not liver cirrhosis or HCC. The ‘Lys-Met’ pattern was identified as a MASLD-risk pattern, with red meats being a representative food source.<h3>Conclusion</h3>Lysine plays a major role in the association between amino acid intake and risk of MASLD. Dietary patterns rich in lysine, such as red meat, could be key targets for MASLD prevention strategies.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"1 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979925","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":"Trends, patterns, and risk factors of esophageal cancer mortality in China, 2008–2021: A national mortality Surveillance System data analysis","authors":"Yunfei Jiao, Tinglu Wang, Lin Fu, Ye Gao, Zhiyuan Cheng, Lei Xin, Jinfang Xu, Han Lin, Wei Wang, Maigeng Zhou, Jinlei Qi, Zhaoshen Li, Luowei Wang","doi":"10.1016/j.jare.2025.05.021","DOIUrl":"https://doi.org/10.1016/j.jare.2025.05.021","url":null,"abstract":"<h3>Introduction</h3>According to the International Agency for Research on Cancer, China had the highest mortality burden of esophageal cancer (EC) globally in 2022.<h3>Objectives</h3>This study aims to analyze the national and provincial trends, patterns, and risk factors of EC deaths in China.<h3>Methods</h3>Data from the National Mortality Surveillance System were used to estimate national and provincial deaths, age-standardized mortality rates (ASMRs), and years of life lost (YLL). An age-period-cohort-based Nordpred model was used to predict trends until 2030. Multilevel Poisson and logistic regression were conducted<!-- --> <!-- -->to assess factors influencing EC mortality and the place of death.<h3>Results</h3>From 2008 to 2021, EC deaths and YLLs decreased from 227,677 to 167,529 and from 5.32 million to 3.50 million, respectively. Meanwhile, the ASMR and age-standardized YLL rate decreased from 24.34 to 11.01 per 100,000 and from 535.91 to 231.08 per 100,000, respectively. By 2030, EC deaths and ASMR are predicted to decline to 150,768 and 7.85 per 100,000, respectively. Nationwide, the average age at death increased from 68.46 to 72.45 years, with an increasing proportion of YLLs in the 65–69 age group. Overall premature mortality was observed to decrease, except for an increase in YLLs among urban populations aged ≥60 years. Higher burdens were observed in rural areas compared to urban areas and among males compared to females. Nationwide, individuals with agriculture-related occupations and lower educational levels exhibited significantly higher risks of EC death. Regions with higher prevalences of smoking and harmful drinking, and lower educational, economic, and medical levels were significantly associated with high mortality. Home was the leading place of EC deaths (80.02 %).<h3>Conclusion</h3>The EC mortality burden in China is decreasing but remains a significant threat to public health. Promoting education, occupational prevention, healthy lifestyles, and medical treatment for targeted populations and regions is essential.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"20 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979922","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":"Overexpression of soybean flavonoid 3′-hydroxylase enhances plant salt tolerance by promoting ascorbic acid biosynthesis","authors":"Jianfei Wu, Xiaokun Wang, Jiawei Xu, Tongtong Li, Guangyao Shan, Li Zhang, Tongdi Yan, Xuejiao Song, Yuxiao Sun, Huihui Guo, Fanchang Zeng","doi":"10.1016/j.jare.2025.05.009","DOIUrl":"https://doi.org/10.1016/j.jare.2025.05.009","url":null,"abstract":"<h3>Introduction</h3>Salt stress is a major cause of crop loss. Soybean (<em>Glycine</em> max), a globally vital legume crop, faces mounting yield constraints due to soil salinization. It is known that the flavonoid biosynthesis pathway involving flavonoid 3′-hydroxylase (F3′H) plays an important role in salt tolerance. However, the precise molecular basis of F3′H-mediated salt tolerance remains inadequately characterized.<h3>Objectives</h3>This study aimed to elucidate the function and explore the pleiotropic molecular basis of F3′H protein in soybean salt tolerance. Innovation on elite new crop varieties facilitates breeding and production applications on salt tolerance.<h3>Methods</h3>We employed CRISPR/Cas9-mediated knockout and <em>Agrobacterium</em>-based overexpression to generate <em>GmF3′H</em> allelic variants and ectopic expression in soybeans. Sanger sequencing and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to confirm the specificity of gene editing and quantify expression levels in overexpression transgenic plants, respectively. As well as Subcellular localization analysis, Yeast two-hybrid (Y2H) assay, LUC activity assay and plant physiological measurements were carried out to elucidate the F3′H-mediated salt tolerance molecular basis in plants.<h3>Results</h3>In this study, we identified the flavonoid 3′ hydroxylase gene (<em>GmF3′H</em>) in soybeans, which as a master regulator of salt stress adaptation during seed germination and seedling stages in both soybean and <em>Arabidopsis thaliana</em>. Furthermore, our study revealed that the evolutionarily conserved F3′H protein competitively binds to the photomorphogenic factor COP9 signalosome subunit 5B (CSN5B) and disrupts its interaction with GDP-mannose pyrophosphorylase 1 (VTC1), a key enzyme in ascorbate biosynthesis. This competitive inhibition redirects metabolic flux toward the L-galactose pathway, leading to an increase in ascorbic acid (AsA) biosynthesis. The enhanced AsA production subsequently improves seedling salt stress tolerance in plants by maintaining redox homeostasis through ROS scavenging.<h3>Conclusion</h3>The discovery and characterization of F3′H-mediated salt tolerance provide a crucial framework for the genetic improvement of crops. This work provides new insights into plant salt stress tolerance and develops innovative strategies to enhance broad-spectrum salt tolerance, a crucial aspect for ensuring food security in crops.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"28 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143979923","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":"Mechanical mechanics-reclaiming a new battlefield for chronic liver disease","authors":"Yiheng Zhang, Tianle Ma, XingXing Lu, Haibing Hua, Li Wu, Zhipeng Chen","doi":"10.1016/j.jare.2025.05.028","DOIUrl":"https://doi.org/10.1016/j.jare.2025.05.028","url":null,"abstract":"<h3>Background</h3>In the 21st century, significant breakthroughs have been made in the research of chronic liver disease. New biochemical markers of pathogenicity and corresponding drugs continue to emerge. However, current treatment strategies remain unsatisfactory due to complex pathological changes in the liver, including vascular dysfunction, myofibroblast-like transition, and local tissue necrosis in liver sinusoids. These challenges have created an urgent need for innovative, synergistic treatments. Mechanical mechanics is a growing field, with increasing evidence suggesting that mechanical signals play a role similar to that of biochemical markers. These signals influence response speed, conduction intensity, and functional diversity in regulating cell activities.<h3>Aim of review</h3>This review summarizes the three main mechanical characteristics involved in the progression of “liver fibrosis-cirrhosis-hepatocellular carcinoma” and provides an in-depth interpretation of several mechanically-related targets. Finally, current and cutting-edge therapeutic strategies are proposed from a cellular perspective. Despite the many challenges that remain, this review is both relevant and significant.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"23 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946253","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":"Anthocyanin accumulation differences in European pears caused by Phytochrome-interacting factor 3 (PcPIF3) promoter mutations under UV-B","authors":"Haowei Cao, Yingying Qu, Lei Guo, Mengjia Wu, Guorong Zhang, Ying Tang, Hongjuan Zhang, Rui Zhai, Chengquan Yang, Lingfei Xu, Zhigang Wang","doi":"10.1016/j.jare.2025.05.010","DOIUrl":"https://doi.org/10.1016/j.jare.2025.05.010","url":null,"abstract":"The phenomenon of red fading in late-stage red-skinned pear fruit development significantly impacts its value. This phenomenon also occurs in ’Starkrimson’, albeit to a lesser extent compared to ’Red Bartlett’ and other varieties. The reasons for the differences in anthocyanin accumulation during the late stages of fruit development in red-skinned European pears varieties are not yet understood. Here, we report a novel pattern of anthocyanin accumulation in response to UV-B in ’Starkrimson’ pears, which is associated with mutations in the <em>PcPIF3</em> promoter. Through transcriptome analysis of ’Red Bartlett’ and ’Starkrimson’ pears, we identified the differentially expressed gene <em>PcPIF3</em>, which is capable of promoting anthocyanin biosynthesis through direct binding to the promoter region of <em>PcMYB10</em>. Under moderate UV-B conditions, the ’Starkrimson’ <em>PcPIF3</em> were significantly increased. By analyzing the <em>PcPIF3</em> promoter regions of different red-skinned pear varieties, we identified the differential binding element as W-BOX 1 and subsequently screened for the upstream positive regulator, PcWRKY11. Y1H and related experiments demonstrated that under UV-B exposure, PcWRKY11 binds specifically to the W-BOX 1 element in the ’Starkrimson’ <em>PcPIF3</em> promoter, thereby enhancing its transcription. These findings indicate that PcWRKY11, in response to UV-B, interacts with the W-BOX 1 element in the ’Starkrimson’ <em>PcPIF3</em> promoter, promoting anthocyanin biosynthesis and mitigating the fading of red coloration in ’Starkrimson’ pears. The difference in the <em>PcWRKY11-PcPIF3</em> module represents a novel mechanism for the variation in anthocyanin accumulation among different red-skinned pear varieties.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"41 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940159","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":"Targeting mesenchymal monocyte-derived macrophages to enhance the sensitivity of glioblastoma to temozolomide by inhibiting TNF/CELSR2/p65/Kla-HDAC1/EPAS1 axis","authors":"Wei Gao, Xinmiao Long, Xiang Lin, Kun Deng, Danyang Li, Meng Huang, Xiangyu Wang, Qing Liu, Minghua Wu","doi":"10.1016/j.jare.2025.05.032","DOIUrl":"https://doi.org/10.1016/j.jare.2025.05.032","url":null,"abstract":"<h3>Introduction</h3>Temozolomide (TMZ) resistance poses a significant challenge to the treatment of aggressive and highly lethal glioblastomas (GBM). Monocyte-derived Macrophages (MDM) within the tumor microenvironment are key factors contributing to TMZ resistance in GBM. Lactate-mediated histone lysine lactylation (Kla) plays a crucial role in the regulation of tumor progression. However, the mechanism through which MDM-induced Kla expression promotes TMZ resistance in GBM remains unclear.<h3>Objectives</h3>The objective of this study s to identify a subtype of MDM with therapeutic potential target and to elucidate the mechanisms through which this subtype of MDM contributes to tumor malignant progression and TMZ resistance.<h3>Methods</h3>We integrated single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics data to evaluate whether mesenchymal (MES) MDM is associated with poor prognosis. By establishing a subtype model of GBM cells for the first time, we validated the mechanism by which MES-MDM promotes subtype conversion of tumor cells. Using patient-derived GBM organoids and an intracranial orthotopic GBM model, we demonstrated that targeting MES-MDMs increased GBM sensitivity to TMZ treatment.<h3>Results</h3>We identified a novel MDM subtype, MES-MDM, in the hypoxic niches of the perinecrotic region characterized by high TREM1 expression, which fueled GBM progression. Hypoxia drived MES-MDM signatures by activating ATF3 transcription. MES-MDM facilitated the transition from the NPC to the MES subtype in GBM cells, in which Histone Deacetylase 1 (HDAC1) Kla, induced by the TNF-CELSR2/p65 signaling pathway, promoted this conversion, thereby promoting TMZ resistance. Targeting MES-MDM with TREM1 inhibitory peptides amplified TMZ sensitivity, offering a potential strategy for overcoming resistance to therapy in GBM. Targeting TREM1 enhanced the effectiveness of anti-PD-1 immunotherapy.<h3>Conclusion</h3>This study provides a potential therapeutic strategy for patients with MES-subtype GBM by targeting MES-MDMs in combination with TMZ or PD-1 antibody treatment.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"17 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946254","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":"An injectable nano-hydroxyapatite-incorporated hydrogel with sustained release of Notoginsenoside R1 enhances bone regeneration by promoting angiogenesis through Notch1/Akt signaling","authors":"Bizhi Tan, Xiao Liu, Shuai Chen, Yan Chen, Zhongyuan He, Zemin Ling, Fangli Huang, Rongcheng Hu, Hao Hu, Xuenong Zou, Fuzhi Ai","doi":"10.1016/j.jare.2025.05.025","DOIUrl":"https://doi.org/10.1016/j.jare.2025.05.025","url":null,"abstract":"<h3>Introduction</h3>Notoginsenoside R1 (NGR1), a bioactive compound, exhibits significant pro-angiogenic potential, making it a promising candidate for treating various diseases. Since angiogenesis and osteogenesis are synergistically coupled processes, NGR1′s capacity to stimulate blood vessel formation may critically promote bone regeneration. However, the underlying molecular mechanisms through which NGR1 promotes angiogenesis in bone repair remain to be fully elucidated.<h3>Objectives</h3>To investigate the potential mechanism by which NGR1 promotes angiogenesis and to validate the therapeutic effect of NGR1-loaded biomaterials on bone defect regeneration.<h3>Methods</h3>Human umbilical vein endothelial cells (HUVECs) were cultured in complete medium containing the screened concentration of NGR1 to investigate its pro-angiogenic phenotype and potential mechanism in <em>vitro</em>. Subsequently, an injectable nano-hydroxyapatite-incorporated GelMA hydrogel was synthesized as an active drug-delivery delivery system for NGR1. The therapeutic effect of this fabricated NGR1-loaded biomaterial on bone defect regeneration was further evaluated in a rat cranial bone defect model. The key molecules in relevant signaling pathways was analyzed by immunohistochemistry.<h3>Results</h3>In <em>vitro</em> experiments demonstrated that NGR1 exhibits good biocompatibility and angiogenic capacity, as it promoted cell proliferation, enhanced cell migration, upregulated the angiogenic-related gene expression, and increased the protein expression of VEGF and VEGFR-2. Furthermore, the implantation of the injectable nano-hydroxyapatite-incorporated GelMA hydrogel loaded with NGR1 significantly enhanced bone defect regeneration in a rat cranial bone defect model compared to hydrogel-only group. Additionally, NGR1 supplementation markedly upregulated CD31 expression during bone formation, suggesting its role in coupling of angiogenesis and osteogenesis. Mechanistically, both in <em>vivo</em> and in <em>vitro</em> experiments indicated that NGR1 likely promote angiogenesis <em>via</em> activating Notch1/Akt singling pathway during bone regeneration.<h3>Conclusions</h3>These findings indicate that NGR1 promotes angiogenesis through Notch1/Akt signaling activation during bone regeneration, which might offer potential therapeutic targets for bone-related diseases. Moreover, the application of NGR1-loaded biomaterials could represent a promising strategy to enhance bone regeneration.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"122 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143946255","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":"NSP6 regulates calcium overload-induced autophagic cell death and is regulated by KLHL22-mediated ubiquitination","authors":"Xingyu Tao, Yanan Wang, Jiangbo Jin, Huilin Yan, Hui Yang, Xiaorui Wan, Ping Li, Yanghua Xiao, Qi Yu, Lingjiao Liu, Yang Liu, Tianyu Han, Wei Zhang","doi":"10.1016/j.jare.2025.05.031","DOIUrl":"https://doi.org/10.1016/j.jare.2025.05.031","url":null,"abstract":"<h3>Introduction</h3>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a substantial global threat. SARS-CoV-2 nonstructural proteins (NSPs) are essential for impeding the host replication mechanism while also assisting in the production and organization of new viral components. However, NSPs are not incorporated into viral particles, and their subsequent fate within host cells remains poorly understood. Additionally, their role in viral pathogenesis requires further investigation.<h3>Objectives</h3>This study aimed to discover the ultimate fate of NSP6 in host cells and to elucidate its role in viral pathogenesis.<h3>Methods</h3>We investigated the effects of NSP6 on cell death and explored the underlying mechanism; moreover, we examined the degradation mechanism of NSP6 in human cells, along with analysing its correlation with coronavirus disease 2019 (COVID-19) severity in patient peripheral blood mononuclear cells (PBMCs).<h3>Results</h3>NSP6 was demonstrated to induce cell death. Specifically, NSP6 interacted with EI24 autophagy-associated transmembrane protein (EI24) to increase intracellular Ca²⁺ levels, thereby enhancing the interactions between unc-51-like autophagy activating kinase 1 (ULK1) and RB1 inducible coiled-coil 1 (RB1CC1/FIP200), as well as beclin 1 (BECN1) and phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3). This cascade ultimately triggers autophagy, thus resulting in cell death. Additionally, we discovered that the homeostasis of the NSP6 protein was regulated by K48-linked ubiquitination. We identified kelch-like protein 22 (KLHL22) as the E3 ligase that was responsible for ubiquitinating and degrading NSP6, restoring intracellular calcium homeostasis and reversing NSP6-induced autophagic cell death. Moreover, NSP6 expression levels were observed to be positively associated with the severity of SARS-CoV-2-induced disease.<h3>Conclusion</h3>This study reveals that KLHL22-mediated ubiquitination controls NSP6 stability and that NSP6 induces autophagic cell death via calcium overload, highlighting its cytotoxic role and suggesting therapeutic strategies that target calcium signaling or promote NSP6 degradation as potential interventions against COVID-19.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"7 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940161","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":"Revealing the multiple faces of LRG1: gene expression, structure, function, and therapeutic potential","authors":"Ding Wang, Di Di, Bo Jiang, Yunlong Wang, Zhenqi Jiang, Yuchen Jing, Huizhe Wu, Shijie Xin","doi":"10.1016/j.jare.2025.05.024","DOIUrl":"https://doi.org/10.1016/j.jare.2025.05.024","url":null,"abstract":"<h3>Background</h3>As the structural characterization of the Leucine-rich alpha-2-glycoprotein 1 (LRG1) protein progresses, its functional diversity has been increasingly unveiled, highlighting its clinical relevance in elucidating disease pathogenesis and identifying potential therapeutic targets.<h3>Aim of review</h3>Grounded in structural biology principles, this review systematically examines the regulatory mechanisms, pathological functions, and intervention strategies associated with LRG1, providing a theoretical foundation for translating these insights into clinical drug therapies.<h3>Key scientific concepts of review</h3>LRG1, distinguished by its leucine-rich repeat motifs, plays a pivotal role in various physiological and pathological processes. This review presents a comprehensive analysis of LRG1′s multifaceted characteristics and its implications in disease. Initially, the regulatory mechanisms modulating <em>LRG1</em> gene expression are detailed, encompassing both transcriptional and post-transcriptional controls. The structural attributes and distributions of LRG1 are subsequently outlined, with an emphasis on the functional relevance of its leucine-rich repeat motifs. Furthermore, the review elaborates on the molecular interactions through which LRG1 engages with distinct receptors, triggering downstream signaling pathways involved in pathological processes. Finally, current therapeutic approaches targeting LRG1 and its receptors are summarized, alongside prospective research avenues for innovative therapeutic development.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"35 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940318","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}