Journal of advanced research最新文献

{"title":"Effect of early packed red blood cell transfusion on sepsis-associated acute kidney injury: A target trial emulation.","authors":"Ting Liu, Weisheng Chen, Xinya Li, Kai Wang, Junjiang Zhu, Xuanhe Tang, Chunbo Chen, Jun Lyu","doi":"10.1016/j.jare.2026.08.009","DOIUrl":"10.1016/j.jare.2026.08.009","url":null,"abstract":"<p><strong>Background: </strong>To date, the effects of packed red blood cell (PRBC) transfusion on sepsis-associated acute kidney injury (SA-AKI) have not been reported in the literature. The objective of this study is to conduct a preliminary exploration of the association between these two factors using a target trial emulation (TTE) that allows for causal inference.</p><p><strong>Methods: </strong>The present study utilized the Medical Information Mart for Intensive Care IV (MIMIC-IV) database, including adult sepsis patients who were admitted to the intensive care unit (ICU) for the first time between 2008 and 2022, with an ICU stay exceeding 24 h. All patients had hemoglobin levels ≤ 10 g/dL within 24 h of sepsis diagnosis. A clone-censor-weight (CCW) approach was employed for target trial emulation (TTE) to evaluate the effects of PRBC transfusion within 24 h of sepsis diagnosis on patient outcomes. The primary outcome was SA-AKI, whereas the secondary outcomes included 7-, 28-, and 90-day mortality. The primary outcome underwent competing risk analysis. The treatment effect was primarily evaluated through differences in SA-AKI risk and survival rate. The 95% confidence intervals (CIs) were calculated using the nonparametric bootstrap method with 1000 repetitions.</p><p><strong>Results: </strong>The present study included a total of 14,869 patients. PRBC transfusion was not significantly associated with the risk of SA-AKI (risk difference: 0.67%, 95% CI: -1.32 to 2.63). However, compared with non-PRBC transfusion, PRBC transfusion significantly enhanced 7-, 28-, and 90-day survival, with significant survival differences of 2.54% (95% CI: 1.68 to 3.46), 4.86% (95% CI: 3.64 to 6.14), and 4.52% (95% CI: 3.06 to 5.97), respectively. Sensitivity analyses produced consistent results.</p><p><strong>Conclusions: </strong>In this study, early PRBC transfusion did not impact the risk of SA-AKI but provided potential benefits in reducing mortality, particularly among sepsis patients with hemoglobin levels ≤ 10 g/dL.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148703087","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":"Screening cross-injury responses in skin organoids identifies a THBS2-enriched pro-repair fibroblast state during regeneration.","authors":"Chao Zhang, Xu Guo, Kehao Ren, Liting Liang, Jianjun Li, Bingyang Yu, Yue Kong, Feng Tian, Muchun He, Zhao Li, Wei Song, Yi Kong, Yuyan Huang, Dongzhen Zhu, Yaxin Tan, Xiangye Yin, Yanlin Su, Xiaobing Fu, Sha Huang","doi":"10.1016/j.jare.2026.08.029","DOIUrl":"10.1016/j.jare.2026.08.029","url":null,"abstract":"<p><strong>Introduction: </strong>Skin injuries impose a substantial global health burden. Conventional wound healing models fail to distinguish evolutionarily conserved regenerative mechanisms from injury specific responses because they cannot capture microenvironmental complexity.</p><p><strong>Objectives: </strong>This study established a high-fidelity mouse skin organoid platform to simulate clinically relevant stressors and identify the core regulatory components of the regenerative program.</p><p><strong>Methods: </strong>Mature skin organoids were individually exposed to hypoxia, hyperthermia, or hyperinflammation. Transcriptomic analysis identified both divergent and convergent responses across diverse injury types. Single-cell RNA sequencing (scRNA-seq) was utilized to characterize fibroblast states in physiological and diabetic wounds.</p><p><strong>Results: </strong>A conserved 85-gene injury-responsive module was identified across all stressors, with thrombospondin 2 (Thbs2) emerging as a highly connected candidate hub within the extracellular matrix (ECM)-remodeling network. Integration with scRNA-seq datasets further showed that Thbs2 expression was enriched in an independently defined pro-repair fibroblast state characterized by ECM remodeling and repair-associated transcriptional features. In the diabetic wound microenvironment, this Thbs2-associated repair signature was attenuated, accompanied by accumulation of intermediate-state fibroblasts.</p><p><strong>Conclusion: </strong>These findings highlight that the acquisition of a specific functional cellular state is closely linked to regeneration. This multi stress platform facilitates the development of universal pro-healing strategies by shifting the focus from molecular targeting to restoring functional cellular states.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148703093","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":"From KRAS inhibition to tumor adaptation: mechanistic layers of resistance and therapeutic strategies.","authors":"Rawan Salih, Fazila Sirajudeen, Mohamed Rahmani","doi":"10.1016/j.jare.2026.08.030","DOIUrl":"10.1016/j.jare.2026.08.030","url":null,"abstract":"<p><strong>Background: </strong>KRAS is a central oncogenic driver in multiple solid malignancies, including non-small cell lung cancer, pancreatic ductal adenocarcinoma, and colorectal cancer. Activating KRAS mutations, together with co-mutations and gene-dosage alterations, reprogram signaling pathways, cellular metabolism, and the tumor microenvironment, thereby promoting aggressive tumor behavior and therapeutic resistance. Despite recent advances, including KRAS G12C inhibitors and emerging agents targeting G12D, pan-RAS(ON), and nucleotide-free RAS, clinical responses remain limited in many KRAS-mutant contexts due to rapid and multifaceted resistance.</p><p><strong>Aim of review: </strong>This review aims to examine the mechanisms underlying resistance to KRAS-targeted therapies and to provide an integrated perspective on how adaptive tumor responses limit the durability of KRAS inhibition.</p><p><strong>Key scientific concepts of review: </strong>Selective pressure from KRAS-targeted therapies drives adaptive tumor evolution through on-target alterations, rewiring of signaling networks, and non-genetic changes in cell state and the tumor microenvironment. This review synthesizes current knowledge on these resistance mechanisms and highlights emerging therapeutic strategies, including rational combination approaches, enhanced RAS pathway suppression, targeted protein degradation, and KRAS-directed immunotherapies. By integrating recent preclinical and clinical advances, this work provides a comprehensive framework for understanding resistance and improving the durability of KRAS pathway inhibition in cancer.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148703110","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":"Pangenomic sequencing and gene-unit genome-wide association study insights into genome plasticity and gene functions in Magnaporthe oryzae.","authors":"Yi Wang, Qi Wu, Jinbin Li, Pei Hu, Qi Liu, Aijia Lin, Runmao Lin, Lina Liu, Chun Wang, Houxiang Kang, Chengyun Li","doi":"10.1016/j.jare.2026.08.020","DOIUrl":"10.1016/j.jare.2026.08.020","url":null,"abstract":"<p><strong>Introduction: </strong>Magnaporthe oryzaeis a model pathogenic fungus that causes serious disease in the two most important staple crops, rice and wheat. Elucidating the genetic variation within natural populations ofM. oryzaeand identifying genes involved in pathogenicity and environmental adaptation are essential for sustainable disease control.</p><p><strong>Objectives: </strong>This study aimed to elucidate the mechanisms underlying genomic variation within the M. oryzae population and to develop a novel GWAS method specifically tailored to this species.</p><p><strong>Methods: </strong>The genomes of M. oryzaediversity population 1 (MDP1), comprising 118 strains, were sequenced andde novoassembled. In addition, a novel gene-unit GWAS (GU-GWAS) method was developed to identify associated loci.</p><p><strong>Results: </strong>Phylogenetic analyses revealed three subgroups among the sequenced strains, which were associated with indica and japonica rice differentiation. We also characterized core and accessory genes in theM. oryzaepopulation through pan-genome analysis. Using GU-GWAS followed by functional validation, we cloned three new genes associated with pathogenesis (SPP1), fungicide tolerance (MoFCS1), and heavy metal tolerance (MoHMT1).</p><p><strong>Conclusion: </strong>This study provides new insights into the pangenome ofM. oryzaeand introduces a method for the identification of functionally important genes in fungal species.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148698538","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":"A least-input nitrogen fertilizer reduction strategy sustains peanut yield with lower nitrogen inputs.","authors":"Yubing Jiao, Ruixia Shen, Manlin Xu, Hui Liang, Lianqiang Jiang, Yong Wang, Yunling Wu, Song Wu, Chao Jia, Yingwen Wang, Binna Lv, Lili Shen, Ying Li, Lixin Zhao, Zonglu Yao, Fei Han, Xiangdong Zhu, Yujun Wang, Jinguang Yang","doi":"10.1016/j.jare.2026.08.025","DOIUrl":"10.1016/j.jare.2026.08.025","url":null,"abstract":"<p><strong>Introduction: </strong>Synthetic nitrogen (N) fertilizers underpin global food security but drive escalating environmental costs, including greenhouse gas (GHG) emissions and soil degradation. Conventional N-reduction strategies face a fundamental trade-off: lowering fertilizer inputs typically compromises crop productivity and farmer income. Nanotechnology offers a pathway to decouple yield from N dependency, yet scalable, low-cost solutions remain elusive.</p><p><strong>Objectives: </strong>This study aimed to develop a least-input foliar fertilization strategy using bio-derived nanocarbon (BNC) that enables a 30% reduction in synthetic N input in peanut (Arachis hypogaea L.) without sacrificing crop yield, nutritional quality, or economic returns, while elucidating the underlying physiological and microbiological mechanisms.</p><p><strong>Methods: </strong>Field trials were conducted with peanut (cv. Huayu 22) over two consecutive growing seasons (2024-2025) in Laixi, Shandong, China, under four treatments: N (conventional N, 100% urea), N-30 (reduced N, 70% urea), N + BNC (100% urea + foliar BNC), and N-30 + BNC (70% urea + 18 g ha^-1 foliar BNC). Photosynthetic parameters, oxidative stress markers, and ¹⁵N isotope tracing were assessed. Transcriptomic, metabolomic, and 16S rRNA microbiome analyses characterized systemic signaling and rhizosphere responses. GHG emissions were modeled using the DNDC framework, and economic benefits were calculated based on yield and input costs.</p><p><strong>Results: </strong>BNC application under N-30% maintained yield parity with the N control by sustaining photosynthetic electron transport and reducing reactive oxygen species (ROS). This enhanced carbon status upregulated the transcription factor HY5, activating nitrate transporter AhNRT1.2 and ammonium transporter AhAMT1.1 and increasing ¹⁵N uptake. Changes in root-exudate composition were accompanied by shifts in the rhizosphere bacterial community, including higher relative abundance of taxa associated with nitrification and nutrient turnover (Nitrospira and Gemmatimonas), and coincided with 21% and 14% higher root NO₃^--N and NH₄⁺-N contents, respectively. Nitrogen use efficiency (NUE) improved by 16.0%, total GHG emissions decreased by 34.8%, and net profit increased by 27.0%.</p><p><strong>Conclusion: </strong>A micro-dosage of upcycled BNC (∼$0.02 ha^-1) orchestrates HY5-mediated shoot-to-root signaling and rhizosphere microbiome restructuring to sustain crop productivity under reduced N inputs. This commercially viable, low-input framework offers a scalable route for climate-smart agriculture that reconciles food security with environmental sustainability.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148698263","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":"Synergistic Janus nanocarrier enables high-deposition fungicide emulsion delivery for enhanced and sustainable control of wheat crown rot.","authors":"Chengying Ding, Lingyan Liu, Xuejian Cheng, Bo Xu, Gangchao Ran, Jing Li, Qiliang Huang","doi":"10.1016/j.jare.2026.08.024","DOIUrl":"10.1016/j.jare.2026.08.024","url":null,"abstract":"<p><strong>Introduction: </strong>The escalating incidence and severity of wheat crown rot poses a profound threat to global wheat yields and food security. Despite widespread fungicide application, the spatial mismatch between deposition sites and pathogen infection loci limits the precision and sufficiency of delivery, thereby reducing disease control efficacy and utilization efficiency, resulting in resource waste and environmental pollution.</p><p><strong>Objectives: </strong>This study aimed to develop a multifunctional fungicidal nano-formulation with high leaf deposition and long-distance transport of active ingredients, in order to enhance the utilization efficiency of the active components.</p><p><strong>Methods: </strong>A functional difenoconazole Pickering emulsion (DIF-PE) with high deposition and delivery efficacy was successfully developed using mesoporous amphiphilic Janus nanoparticles. These nanoparticles (PEG@PDA@CaP) composed of hydrophobic calcium phosphate (CaP) integrated with hydrophilic polydopamine modified with methoxy poly (ethylene glycol) thiol, served as both solid emulsifiers and functional carriers. Interface behavior and transport performance were characterized using theoretical calculations, HPLC-MS/MS, SEM, TEM, CLMS, and ICP‑OES.</p><p><strong>Results: </strong>Electrostatic interaction (E =  - 64.24 kcal/mol) between PEG@PDA@CaP and wheat leaves imparts DIF-PE with exceptional foliar deposition and adhesion. Compared to commercialized difenoconazole emulsion (DIF-EW), DIF-PE achieved 79.73% greater foliar deposition and 63.84% higher rainfastness. Enhanced deposition and penetration, together with the synergistic transport facilitated by PEG@PDA@CaP, collectively promoted more efficient downward delivery of difenoconazole, root and stem difenoconazole concentrations in treated plants were 6.95-fold and 2.34-fold higher than in controls at 24 h, respectively. Ultimately, DIF-PE improved the control efficacy against wheat crown rot by 19.15% relative to DIF-EW, with no adverse effects on plant growth.</p><p><strong>Conclusion: </strong>This nanocarrier-formulation system significantly improved the efficacy of conventional formulations, and broadened the applicability of nanocarriers, providing a powerful strategy for green management of crop diseases.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148698604","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":"Hepatocyte VDR protects against cirrhosis-associated bone loss via repression of the FN1/Integrin αv signaling.","authors":"Li Cen, Chenxi Tang, Bingru Lin, Xin Song, Xiaofeng Zhang, Peihao Liu, Chengfu Xu, Chaohui Yu","doi":"10.1016/j.jare.2026.08.006","DOIUrl":"10.1016/j.jare.2026.08.006","url":null,"abstract":"<p><strong>Introduction: </strong>Vitamin D and its receptor (VDR) are essential for liver homeostasis and bone development, and their dysfunction has been implicated in cirrhosis-associated osteoporosis.</p><p><strong>Objectives: </strong>This study aimed to elucidate the molecular mechanisms linking hepatic injury to bone fragility.</p><p><strong>Methods: </strong>We examined VDR dysfunction in cirrhotic patients and in a murine model of cirrhosis. Hepatocyte-specific VDR knockout mice were used to determine the contribution of hepatic VDR to bone loss during cirrhosis.</p><p><strong>Results: </strong>Analysis of UK Biobank data, a Chinese patient cohort, and murine cirrhosis models demonstrated that reduced serum 25-hydroxyvitamin D (25-OHD) correlates with hepatic fibroinflammation and low bone mass. However, vitamin D₃ supplementation failed to restore bone density, indicating noncanonical VDR signaling in bone homeostasis. Hepatic VDR expression declined with progressive fibrosis, and hepatocyte-specific VDR deletion exacerbated trabecular bone loss through enhanced osteoclastogenesis without altering bone formation. Mechanistically, VDR deficiency upregulated hepatocyte fibronectin (FN1), which trafficked to bone marrow and activated osteoclasts via integrin αv. Serum FN1 levels were elevated in cirrhosis patients, correlated with reduced vertebral bone density, and associated with osteoclast activity in mice. Genetic ablation or hepatocyte-specific knockdown of FN1 attenuated bone resorption and improved trabecular architecture. Pharmacologic inhibition of the FN1-integrin αv pathway with CWHM12 reduced osteoclast activity, rescued bone mass, and concurrently ameliorated hepatic fibrosis.</p><p><strong>Conclusion: </strong>These findings establish hepatic VDR as a central modulator of cirrhosis-associated osteoporosis through FN1-mediated integrin signaling. Targeting the VDR-FN1-integrin αv axis offers a dual therapeutic opportunity for managing both hepatic fibrosis and osteoporosis in cirrhosis.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148698566","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":"NUDT2 and a proteome-wide causal map of plasma proteins in osteoporosis.","authors":"Zhen Wang, Sixu Chen, Junjie Luo, Zhengbo Liu, Jing Wen, Binyang Feng, Wen-Hao Ye, Jian-Chao Ma, Zhenyue Chen, Zhen Li, Zhenwen Yang, Junxiang Qiu, Zhong-Kai Cui","doi":"10.1016/j.jare.2026.08.023","DOIUrl":"10.1016/j.jare.2026.08.023","url":null,"abstract":"<p><strong>Introduction: </strong>Pharmacological targets supported by genetic evidence demonstrate significantly higher success rates in clinical development. Osteoporosis (OP) represents a major global health burden; however, the causal plasma proteome underlying OP remains largely unexplored, limiting the discovery of effective circulating biomarkers and therapeutic agents.</p><p><strong>Objectives: </strong>This study aimed to conduct a comprehensive proteome-wide analysis to construct a causal map of plasma proteins for OP and to identify high-confidence therapeutic targets with translational potential.</p><p><strong>Methods: </strong>We performed a proteome-wide Mendelian randomization (PW-MR) analysis by integrating large-scale GWAS meta-analysis data (18,008 OP cases and 928,650 controls) with cis-acting protein quantitative trait loci (pQTLs) derived from the deCODE and UKB-PPP cohorts. To ensure robustness, we employed orthogonal validation approaches, including colocalization analyses, summary data-based Mendelian randomization (SMR), and single-cell transcriptomic mapping.</p><p><strong>Results: </strong>We identified 144 plasma proteins causally associated with OP, encompassing two novel susceptibility loci (HOXC5 and HBQ1) and five previously unreported candidates (NUDT2, NUB1, TNFSF8, UNG, and MXRA8). Notably, single-cell mapping revealed that NUDT2 is specifically enriched in osteoprogenitor cells, distinct from other identified targets.</p><p><strong>Conclusion: </strong>These findings delineate the first causal blueprint of the OP plasma proteome. NUDT2 is highlighted as a plausible metabolic regulator of bone formation. Collectively, this study provides a valuable resource for precision diagnostics and accelerates the development of novel therapeutics for OP.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148698621","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":"Resolvin D₁ alleviates periodontitis by promoting FPR2-dependent macrophage pro-resolving polarization and efferocytosis.","authors":"Xuan-Xuan Yu, Zi-Yao Zhuang, Rui-Yang Ge, Shuang Lin, Jiang-Yan Ren, Yi-Wen Zhou, Jing-Lun Zhang, Zi-Xuan Li, Ge-Fei Li, Jun Ji, Fuhua Yan, Huang Li, Jie Deng","doi":"10.1016/j.jare.2026.08.001","DOIUrl":"10.1016/j.jare.2026.08.001","url":null,"abstract":"<p><strong>Introduction: </strong>Periodontitis is a chronic inflammatory disease driven by dysregulated host responses and failed resolution of inflammation, leading to progressive periodontal tissue destruction. This resolution failure is critically linked to impaired macrophage efferocytosis and a deficiency in endogenous specialized pro-resolving mediators such as Resolvin D₁ (RvD₁).</p><p><strong>Objectives: </strong>This study aimed to determine if exogenous RvD₁ can restore periodontal homeostasis and to define the formyl peptide receptor 2 (FPR2)-dependent mechanisms governing macrophage reprogramming and the clearance of necroptotic cells.</p><p><strong>Methods: </strong>We integrated two independent human single-cell RNA sequencing (scRNA-seq) datasets from gingival and periodontal tissues, with a murine ligature-induced periodontitis model using wild-type (Fpr2^fl/fl) and myeloid-specific Fpr2 conditional knockout (Fpr2^Lyz2-cKO) mice. Therapeutic efficacy was assessed via scRNA-seq, micro-CT, and histology, while downstream molecular pathways were validated through in vivo and ex vivo plus in vitro macrophage functional and signaling assays.</p><p><strong>Results: </strong>Human scRNA-seq analysis revealed a resolution-deficient immune landscape in periodontitis, characterized by impaired macrophage efferocytosis, increased necroptotic signatures, and reduced RvD₁ biosynthetic capacity; these abnormalities were largely reversed following periodontal therapy. In vivo, RvD₁ significantly reduced alveolar bone loss and decreased necroptotic burden in Fpr2^fl/fl mice but not in Fpr2^Lyz2-cKO mice. Single-cell profiling demonstrated that RvD₁ remodeled the myeloid compartment, promoting monocyte differentiation toward pro-resolving macrophages marked by elevated expression of Chil3, Fn1, and Arg1. Pseudotime trajectory mapping, corroborated by functional engulfment assays, identified an RvD₁-induced efferocytosis-competent macrophage state. Mechanistically, RvD₁ suppressed the p38 mitogen-activated protein kinase (MAPK)-ADAM17 signaling axis, preventing CD14 cleavage and enhancing recognition and clearance of necroptotic cells. Deletion of Fpr2 in myeloid lineage cells abolished these effects.</p><p><strong>Conclusions: </strong>This study proposes an RvD₁-FPR2-p38 MAPK/ADAM17-CD14 axis that integrates macrophage reprogramming with efficient efferocytotic clearance to resolve periodontal inflammation. Targeting this pathway represents a host-directed immunomodulatory strategy for the treatment of periodontitis and potentially other chronic inflammatory diseases.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148698612","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":"DACH1 SUMOylation protects against diabetic cardiomyopathy by suppressing endoplasmic reticulum stress.","authors":"Jie Lin, Na Liu, Bo Li, Yi Wang, Congye Li, Yue Yin, Heng Ma, Lu Yu, Jie Zhou","doi":"10.1016/j.jare.2026.08.026","DOIUrl":"10.1016/j.jare.2026.08.026","url":null,"abstract":"<p><strong>Introduction: </strong>Endoplasmic reticulum (ER) stress is a key driver of diabetic cardiomyopathy (DCM), but its upstream regulators are incompletely defined. The transcription factor DACH1 is genetically linked to diabetes and cardiovascular risk, yet its role in the diabetic heart is unknown.</p><p><strong>Objectives: </strong>This study aimed to elucidate the function and post-translational regulation of DACH1 in DCM, focusing on its interplay with ER stress.</p><p><strong>Methods: </strong>Cardiac function, ER stress, and apoptosis were assessed in db/db mice and high glucose-treated cardiomyocytes. AAV9 was used for cardiac-specific DACH1 overexpression in vivo. SUMOylation and ubiquitination of DACH1 were analyzed via co-immunoprecipitation, mutagenesis, and proteasome inhibition assays.</p><p><strong>Results: </strong>Myocardial DACH1 protein, but not its mRNA, was significantly reduced in experimental DCM. Restoring cardiac DACH1 alleviated dysfunction, ER stress, apoptosis, and fibrosis in diabetic mice. DACH1 stability was associated with SUMOylation at lysines K348, K599, and K631, and TRIM28 facilitated this modification in our experimental system. This modification was reduced under diabetic conditions and was associated with increased ubiquitin-proteasome degradation of DACH1. Enhancing SUMO1 increased DACH1 stability, helped preserve DACH1 nuclear retention, and protected cardiomyocytes from high glucose-induced ER stress and apoptosis.</p><p><strong>Conclusion: </strong>Impaired SUMOylation may contribute to DACH1 depletion in the diabetic heart. SUMOylation-dependent stabilization of DACH1 represents a potential cardioprotective pathway that mitigates diabetic myocardial injury by suppressing ER stress.</p>","PeriodicalId":94063,"journal":{"name":"Journal of advanced research","volume":" ","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148698299","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}