Translational Research最新文献

{"title":"PHGDH alleviates DKD by regulating YB1/SLC7A11-mediated ferroptosis in podocytes","authors":"Yinghui Wang ,&nbsp;Qingqing Zhang ,&nbsp;Shasha Lv ,&nbsp;Xueling Wang ,&nbsp;Qingzhen Liu ,&nbsp;Xiangchun Liu ,&nbsp;Yaping Zhang ,&nbsp;Gang Liu","doi":"10.1016/j.trsl.2025.06.001","DOIUrl":"10.1016/j.trsl.2025.06.001","url":null,"abstract":"<div><div>Diabetic kidney disease (DKD) is a main cause of end-stage renal disorder, yet its pathogenesis is still incompletely understood. Ferroptosis has been implicated in DKD progression; however, its regulatory mechanisms remain unclear. Phosphoglycerate dehydrogenase (PHGDH), a key enzyme in serine biosynthesis, has been minimally studied in DKD development. To elucidate the roles of PHGDH in ferroptosis and its underlying mechanism in podocytes and DKD, we conducted this study. Our findings demonstrate that PHGDH deficiency exacerbates podocyte injury, characterized by cytoskeletal disorganization, and promotes ferroptosis in both podocytes and DKD renal tissues. Conversely, PHGDH overexpression alleviates podocyte injury, reduces ferroptosis, and improves renal function in DKD mice. Mechanistically, we identified that PHGDH mediates ferroptosis by regulating SLC7A11 expression, a key ferroptosis-related protein. Specifically, PHGDH stabilizes Y-box binding protein 1 (YB1) by inhibiting its K48-linked ubiquitination and degradation, thereby enhancing SLC7A11 mRNA stability and expression. In conclusion, our study reveals a novel PHGDH-YB1-SLC7A11 regulatory axis that is responsible for suppressing ferroptosis and protecting against podocyte and renal injury in DKD. Our findings shed new light into the molecular mechanism underlying ferroptosis in DKD and highlight PHGDH as a therapeutic target for mitigating ferroptosis-mediated renal damage.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"282 ","pages":"Pages 1-13"},"PeriodicalIF":6.4,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetically targeting PRMT5 promotes antitumor immunity by inducing endogenous retroviruses expression and triggering viral mimicry response","authors":"Hua Zhang ,&nbsp;Gang Shi ,&nbsp;Yamei Li ,&nbsp;Chao Wang ,&nbsp;Yong Zhang ,&nbsp;Yan Luo ,&nbsp;Jia Xu ,&nbsp;Yusha Qiu ,&nbsp;Jinhu Ma ,&nbsp;Jin Yang ,&nbsp;Dandan Liao ,&nbsp;Yihua Chen ,&nbsp;Hongxin Deng","doi":"10.1016/j.trsl.2025.05.007","DOIUrl":"10.1016/j.trsl.2025.05.007","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is one of the most common cancers worldwide. Although immune checkpoint blockade (ICB) has transformed CRC treatment, the low response rate and immune resistance remain significant challenges. In recent years, epigenetic therapies have been shown to induce viral mimicry response to overcome immune resistance and increase the effectiveness of ICB. However, as an epigenetic modifier, the intrinsic function of PRMT5 in controlling innate immune signaling, viral mimicry, and the tumor microenvironment in CRC remains to be elucidated. Here, we report that PRMT5 inhibition attenuates CRC growth and epigenetically targeting PRMT5 remolds the tumor immune microenvironment, thereby enhancing the therapeutic efficacy of ICB. Mechanistically, PRMT5 knockdown increases endogenous retroviruses (ERVs) expression and dsRNA formation and causes DNA repair incompetence and genomic instability. These changes, combined with the elevated expression of RIG-I/MDA5/STING, trigger innate immune activation and viral mimicry response, thereby facilitating immune cell infiltration and enhancing ICB effectiveness. Furthermore, PRMT5 knockdown reduces H3R2me2s and H3R8me2s levels, and epigenetically promotes innate immune responses. Our study reveals the tumor intrinsic role of PRMT5 in controlling ERVs and innate sensors expression, providing perspectives for the epigenetically targeting of PRMT5 to induce viral mimicry response and enhance antitumor immunity in CRC.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"281 ","pages":"Pages 55-68"},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel rabbit model of severe ARDS: Synergistic effects of acid aspiration and harmful mechanical ventilation","authors":"Petra Košútová ,&nbsp;Nikollet Nemcová ,&nbsp;Maroš Kolomazník ,&nbsp;Andrea Čalkovská ,&nbsp;Pavol Mikolka","doi":"10.1016/j.trsl.2025.05.009","DOIUrl":"10.1016/j.trsl.2025.05.009","url":null,"abstract":"<div><h3>Background</h3><div>Acute respiratory distress syndrome (ARDS) is characterised by severe inflammation and pulmonary edema, often leading to respiratory failure. This study aims to develop a stable and relevant rabbit model of severe ARDS using hydrochloric acid (HCl) aspiration and ventilator-induced lung injury (VILI).</div></div><div><h3>Methods</h3><div>Adult New Zealand rabbits were divided into four groups: Saline (<em>n</em> = 9), 1-hit 3.0 (HCl 3 ml/kg, <em>n</em> = 7), 1-hit 6.0 (HCl 6 ml/kg, <em>n</em> = 7), and 2-hit (HCl 3 ml/kg and ventilation with V_T 20 ml/kg, zero PEEP, RR 20-30 bpm, and FiO₂ 1.0 to mimic VILI, <em>n</em> = 14). PaO₂/FiO₂ ratio, oxygenation index, oxygen saturation, PaCO₂, ventilation efficiency index and alveolar-arterial gradient were evaluated every hour for 4 h after induction of lung injury. The <em>post-mortem</em> analysis included total and differential cell counts in bronchoalveolar lavage fluid (BALF), evaluation of lung edema formation, biochemical and histological examination of lung tissue<em>.</em></div></div><div><h3>Results</h3><div>In the 2-hit group, we observed a significant deterioration of all lung function parameters (P/F ratio, oxygenation index, ventilation efficiency index, and alveolar-arterial gradient) compared to the saline group. Similarly, a deterioration was observed in the 1-hit 6.0 group. When analysing the inflammatory profile, we observed significantly increased levels of chemokines and cytokines (TNFα, IL-1β, IL-6, IL-8, ET-1, MCP, H1F, MIP) and oxidative stress parameters (3NT, MDA, AOPP, catalase and GSH/GSSG) in BALF in the 2-hit group compared to the saline group. Intratracheal administration of HCl alone did not have a significant impact on inflammation as the combination of two insults. An increased wet-to-dry lung weight ratio (W/D), indicative of pulmonary edema, was observed in both the 2-hit and 1-hit 6.0 groups compared to the saline group. An increased level of protein content in BALF and total lung injury score were observed in the 2-hit group compared to the saline group, 1-hit 3.0 and 1-hit 6.0.</div></div><div><h3>Conclusion</h3><div>The combination of hydrochloric acid aspiration and ventilator-induced lung injury reliably reproduces key features of severe ARDS, offering a robust and clinically relevant model for investigating its complex pathophysiology and evaluating novel therapeutic interventions.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"281 ","pages":"Pages 43-54"},"PeriodicalIF":6.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144192639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Information for Readers","authors":"","doi":"10.1016/S1931-5244(25)00060-X","DOIUrl":"10.1016/S1931-5244(25)00060-X","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"280 ","pages":"Page IBC"},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Author Guidelines","authors":"","doi":"10.1016/S1931-5244(25)00059-3","DOIUrl":"10.1016/S1931-5244(25)00059-3","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"280 ","pages":"Pages iii-iv"},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial Advisory Board","authors":"","doi":"10.1016/S1931-5244(25)00058-1","DOIUrl":"10.1016/S1931-5244(25)00058-1","url":null,"abstract":"","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"280 ","pages":"Page ii"},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144147890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive modeling of ARDS mortality integrating biomarker/cytokine, clinical and metabolomic data","authors":"Ruslan Rafikov ,&nbsp;Debrah M. Thompson ,&nbsp;Olga Rafikova ,&nbsp;Sara M. Camp ,&nbsp;Roberto A. Ribas ,&nbsp;Ramon C. Sun ,&nbsp;Matthew S. Gentry ,&nbsp;Nancy G. Casanova ,&nbsp;Joe G N Garcia","doi":"10.1016/j.trsl.2025.05.005","DOIUrl":"10.1016/j.trsl.2025.05.005","url":null,"abstract":"<div><div>Acute Respiratory Distress Syndrome (ARDS), characterized by the rapid onset of respiratory failure and mortality rates of ∼40%, remains a significant challenge in critical care medicine. Despite advances in supportive care, accurate prediction of ARDS mortality remains challenging, resulting in delayed delivery of targeted interventions and effective disease management. Traditional critical illness severity scores lack specificity for ARDS, underscoring the need for more precise prognostic tools for ARDS mortality. To address this crucial gap, we employed a multimodal approach to predict ARDS patients utilizing a comprehensive dataset comprised of integrated clinical, metabolomic, and biochemical/cytokine data from ARDS patients (collected within hours of ICU admission) to develop and validate predictive models of ARDS mortality risk. The most robust multimodal data model generated demonstrated superior predictive capability with an area under the curve (AUC) of 0.868 on the test set and 0.959 on the validation set. Notably, this model achieved perfect specificity in identifying non-survivors in the validation cohort, highlighting potential utility in guiding early and targeted interventions in ICU settings. Metabolomic analysis revealed significant alterations in crucial pathways associated with ARDS mortality with tryptophan metabolism, particularly the kynurenine pathway, emerging as the most significantly enriched metabolic route, as well as the NAD+ metabolism/nicotinamide phosphoribosyltransferase (NAMPT) and glycosaminoglycan biosynthesis pathways. These metabolic derangements were strongly confirmed by lipidomic/metabolomic analysis of lung tissues from a porcine sepsis/ARDS model. Together, these findings demonstrate the promise of integrating multimodal data to improve ARDS prognostication and to provide important insights into the complex metabolic derangements underlying severe ARDS. Identification of metabolic signatures, such as kynurenine and NAD+ metabolism/NAMPT pathways, may serve as a foundation for developing personalized and effective targeted interventions and management strategies for ARDS patients.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"281 ","pages":"Pages 31-42"},"PeriodicalIF":6.4,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"sFRP5 ameliorates atherosclerosis by suppressing the JNK/TLR9 pathway in macrophages","authors":"Yue Yu ,&nbsp;Han Chen ,&nbsp;Rui Wang ,&nbsp;Fei Xu,&nbsp;Jiasheng Yin,&nbsp;Tongtong Zang,&nbsp;Changyi Zhou,&nbsp;Chengpeng Liu,&nbsp;Chaofu Li,&nbsp;Li Shen,&nbsp;Junbo Ge","doi":"10.1016/j.trsl.2025.05.004","DOIUrl":"10.1016/j.trsl.2025.05.004","url":null,"abstract":"<div><div>Secreted frizzled related protein 5 (sFRP5), an anti-inflammatory adipokine, plays a crucial role in various diseases, and its serum levels are low in patients with coronary artery disease (CAD). However, its role in atherosclerosis remains unclear. Therefore, we investigated the correlation between sFRP5 and plaque stability, along with the molecular mechanisms underlying atherosclerosis. In patients with CAD, serum sFRP5 levels were positively correlated with plaque stability, a predictor of thin-cap fibroatheromas (TCFAs). Recombinant sFRP5 (r-sFRP5) supplementation significantly increased plaque stability and ameliorated atherosclerosis progression in <em>ApoE^-/-</em> mice. Aortic RNA-sequencing (RNA-seq) revealed sFRP5-mediated regulation in inflammatory cells. Our experiments confirmed that sFRP5 inhibits inflammation and macrophage migration. Mechanistically, Toll-like receptor 9 (TLR9) was identified as a downstream target of sFRP5, and sFRP5 suppressed TLR9 expression by decreasing c-Jun N-terminal kinase (JNK) phosphorylation. These findings suggest that serum sFRP5 levels are associated with plaque stability and play a protective role in atherosclerosis by attenuating inflammation and macrophage infiltration via inhibition of the JNK/TLR9 pathway, thereby ameliorating the progression of atherosclerosis. This study highlights the potential of sFRP5 as both a biomarker and therapeutic target for plaque stability in atherosclerosis.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"281 ","pages":"Pages 1-13"},"PeriodicalIF":6.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144133401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of adipose-derived stem cell-derived extracellular vesicles affecting macrophage efferocytosis by mediating ADAM17/MerTK in the apoptosis of tubular epithelial cells after sepsis-associated acute kidney injury","authors":"Zhixiang Bian,&nbsp;Xiangxiang Wang,&nbsp;Xiaoxuan Su,&nbsp;Ming Yang,&nbsp;Rui Zhu,&nbsp;Shunjie Chen","doi":"10.1016/j.trsl.2025.05.002","DOIUrl":"10.1016/j.trsl.2025.05.002","url":null,"abstract":"<div><h3>Objective</h3><div>This study explored the molecular mechanism of adipose-derived stem cell-derived extracellular vesicles (ADSC-EVs) improving post-sepsis-associated acute kidney injury (S-AKI) tubular epithelial cell (TEC) apoptosis by modulating ADAM17/MerTK-mediated macrophage efferocytosis.</div></div><div><h3>Methods</h3><div>The S-AKI mouse model was established by caecal ligation and puncture and intravenously injected with ADSC-EVs. Mouse kidney macrophages were cultured with LPS, cultured with EVs while transfecting with oe-ADAM17 or si-MerTK, then incubated with Jurkat cells. Mouse serum urea and creatinine, and KIM-1, efferocytosis- and apoptosis-related protein, inflammatory factor, cytokine, and soluble MerTK (sMerTK) levels were determined using colorimetric assay, immunohistochemistry, Western blot, and ELISA. Renal tubular injury, TEC apoptosis, macrophage efferocytosis, and M1/M2 polarization levels were assessed via HE staining, TUNEL staining, immunofluorescence, and flow cytometry, respectively. <em>In vivo</em> validation experiments were conducted.</div></div><div><h3>Results</h3><div>S-AKI mice displayed elevated levels of serum urea, creatinine, KIM-1, pro-inflammatory factors, pro-apoptotic proteins and ADAM17 protein, decreased anti-apoptotic protein and MerTK protein levels, and diminished M2 polarization. ADSC-EVs down-regulated ADAM17 and sMerTK, and increased cell membrane MerTK, macrophage recognition of apoptotic cells and efferocytosis, and M2 polarization in renal tissues of S-AKI mice and LPS-induced mouse renal macrophages, indicating that ADSC-EVs regulated ADAM17/MerTK-mediated macrophage efferocytosis and promoted M2 polarization. MerTK silencing partially reversed ADSC-EVs-regulated LPS-induced mouse renal macrophage efferocytosis and M2 polarization. <em>In vivo</em>, ADAM17 upregulation partly averted ADSC-EVs-regulated post-S-AKI TEC apoptosis in mouse renal tissues.</div></div><div><h3>Conclusion</h3><div>ADSC-EVs down-regulated sMerTK level and up-regulated macrophage membrane MerTK protein level by modulating ADAM17 to promote macrophage efferocytosis and ameliorate post-S-AKI TEC apoptosis and inflammation.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"281 ","pages":"Pages 14-30"},"PeriodicalIF":6.4,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling diabetic epitheliopathy using 3D-Organotypic corneal epithelium","authors":"Grazia Maugeri ,&nbsp;Agata Grazia D’Amico ,&nbsp;Salvatore Saccone ,&nbsp;Francesca Bruno ,&nbsp;Elisabetta Pricoco ,&nbsp;Davide Scollo ,&nbsp;Teresio Avitabile ,&nbsp;Antonio Longo ,&nbsp;Velia D’Agata","doi":"10.1016/j.trsl.2025.05.003","DOIUrl":"10.1016/j.trsl.2025.05.003","url":null,"abstract":"<div><div>Diabetic keratopathy (DK) is a degenerative corneal disease occurring in more than 50 % of diabetic patients. DK is correlated with the hyperglycemic state causing morphological and functional changes in corneal layers. Currently, most studies on the cornea are performed on two-dimensional (2D) cultures <em>in vitro</em> or animal models. Although 2D culture models can provide large amounts of data at low cost, they poorly represent the complex pathophysiology of the human cornea and hardly predict <em>in vivo</em> responses that can be achieved with animal model studies. However, the use of the latter presents ethical problems. Therefore, it is necessary to identify new strategies and models that can integrate the information validly and effectively, to reduce the number of animals used. Here, we used human corneal epithelial cells (hCECs) derived from donor cornea differentiated into three-dimensional (3D)-organotypic air-liquid interface (ALI), which resemble the features of the corneal epithelium. The 3D-organotypic ALI corneal epithelium was subjected to high-glucose conditions to generate a model of diabetic epitheliopathy. Our model showed well-established molecular and cellular characteristics of this pathology, such as epithelial defects and inflammation, with increased expression of IL-1β, TNF-<span><math><mi>α</mi></math></span>, p-NF-kB, COX-2, MMP-2 and MMP-9. The data provided highlight the utility of 3D-organotypic corneal epithelium in modeling diabetic epitheliopathy, offering new avenues in drug screening, as well as in precision and personalized medicine.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"280 ","pages":"Pages 55-63"},"PeriodicalIF":6.4,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144103120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}