Frontiers in bioscience (Landmark edition)最新文献

{"title":"Calcium-Sensing Receptor Activation Disrupts Phosphatidylserine Asymmetry and Promotes Calcium Oxalate Crystal-Induced Epithelial Injury in Renal Tubular Epithelial Cells.","authors":"Hanlin Liu, Yangjie Xiao, Yuqiang Fu, Siyu Chen, Wei Shi, Xiaoran Li","doi":"10.31083/FBL53201","DOIUrl":"https://doi.org/10.31083/FBL53201","url":null,"abstract":"<p><strong>Background: </strong>Calcium oxalate (CaOx) crystal retention on the renal tubular epithelium is a key step in urolithiasis. Phosphatidylserine (PS) exposure may facilitate crystal-cell adhesion, but the upstream signaling mechanisms and the relative contributions of impaired inward PS flipping versus outward PS redistribution remain unclear.</p><p><strong>Materials and methods: </strong>Global proteomic profiling using 2-dimensional electrophoresis and matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (2-DE/MALDI-TOF/TOF) in an immortalized human proximal tubular epithelial cell line (HK-2) cells exposed to calcium oxalate monohydrate (COM) identified upregulation of the calcium-sensing receptor (CaSR). HK-2 cells were treated with COM with or without the CaSR antagonist NPS2390 or the CaSR agonist gadolinium chloride (GdCl₃). Bidirectional PS transport was assessed using an N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) (NBD)-labeled phosphatidylserine (NBD-PS) fluorescence-quenching assay, and surface PS exposure was measured by annexin V binding. Aminophospholipid translocase (APLT) expression, APLT-dependent inward PS transport, crystal adhesion, oxidative stress, and apoptosis-related signaling were evaluated.</p><p><strong>Results: </strong>COM increased CaSR expression, enhanced surface PS exposure, and promoted crystal adhesion with concurrent oxidative stress and apoptosis-related signaling. COM induced a CaSR-sensitive defect in APLT-dependent inward PS flipping: NPS2390 partially restored inward PS transport and APLT expression, whereas GdCl₃ exacerbated these changes. In contrast, COM-enhanced outward PS redistribution and externalization was largely unaffected by CaSR modulation, indicating relative CaSR insensitivity of the outward process. Consistently, CaSR activation aggravated, while CaSR inhibition attenuated, crystal adhesion and injury-related readouts.</p><p><strong>Conclusions: </strong>COM was associated with enhanced crystal-cell adhesion, CaSR activation, and a CaSR-sensitive impairment of APLT-dependent inward PS flipping, whereas enhanced outward PS redistribution appeared largely CaSR-insensitive. Pharmacologic inhibition of CaSR attenuated epithelial injury and crystal retention-related readouts, suggesting that CaSR may represent a potential therapeutic target.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"53201"},"PeriodicalIF":3.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889548","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":"Itaconic Acid and Its Isomers Ameliorate Renal Ischemia-Reperfusion Injury in Rats by Inhibiting NLRP3-Mediated Inflammation.","authors":"Bin Tang, Zhijian Luo","doi":"10.31083/FBL52184","DOIUrl":"https://doi.org/10.31083/FBL52184","url":null,"abstract":"<p><strong>Background: </strong>Itaconic acid and its isomers citraconic acid and mesaconic acid are a recently identified class of metabolites with anti-inflammatory and antioxidant effects. This study investigates their roles in ischemia-reperfusion-induced acute kidney injury.</p><p><strong>Methods: </strong>In this study, a rat model of renal ischemia-reperfusion injury (IRI) was established, and itaconic acid, citraconic acid and mesaconic acid were administered as a preoperative intervention. After the operation, renal injury was evaluated by contrast-enhanced ultrasound, biochemical analyses and histopathological staining.</p><p><strong>Results: </strong>The intervention with itaconic acid and its isomers reduced the production of the inflammatory cytokines interleukin-18 (IL-18) (<i>p</i> < 0.05), inhibited activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome (<i>p</i> < 0.05), and reduced reactive oxygen species levels (<i>p</i> < 0.05). The intervention with itaconic acid and mesaconic acid reduced the production of the inflammatory cytokine interleukin-1β (IL-1β) (<i>p</i> < 0.05). The expression of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) spot protein in the intervention group was significantly lower than that in the renal ischemia-reperfusion injury (IRI) group (<i>p</i> < 0.01).</p><p><strong>Conclusions: </strong>These findings suggest that itaconic acid, citraconic acid, and mesaconic acid may be potential therapeutic agents for renal ischemia-reperfusion through their anti-inflammatory and antioxidant effects.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"52184"},"PeriodicalIF":3.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889050","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":"Aging and Reproductive Cancers: An Integrative View on Cell-Free DNA and Transposable Elements.","authors":"Monia Cecati, Salvatore Vaiasicca, Laura Cianfruglia, Stefania Fumarola, Roberto Campagna, Francesca Marchegiani, Maurizio Cardelli","doi":"10.31083/FBL50970","DOIUrl":"https://doi.org/10.31083/FBL50970","url":null,"abstract":"<p><p>Aging is one of the strongest risk factors for cancer, and its impact is particularly evident in malignancies of the reproductive system. Ovarian, endometrial, cervical, vulvar, prostate, and penile cancers are mainly diagnosed in older adults and often show different clinical and biological features compared with the same tumors in younger patients. Aging is associated with hormonal changes, immune decline, epigenetic alterations, and accumulation of DNA damage, all of which contribute to cancer development and progression. At the same time, many older patients have frailty and multiple comorbidities, which can limit the use of screening programs and invasive diagnostic procedures. This often leads to delayed diagnosis and worse outcomes. Cell-free DNA (cfDNA) is a minimally invasive biomarker that can be obtained from blood samples and provides molecular information on both tumor and host tissues. Circulating DNA reflects tumor-specific alterations but is also influenced by aging-related changes in DNA release, fragmentation, and methylation. For this reason, aging must be considered when cfDNA-based biomarkers are applied in clinical practice. In this review, we describe how aging influences the biology of reproductive system cancers and how these processes are mirrored in cfDNA profiles. We focus on the clinical use of cfDNA for cancer detection and monitoring in older and fragile patients. Special attention is given to repetitive elements in cfDNA, which are strongly affected by aging and tumor-related epigenetic changes and can be detected with high sensitivity even when the tumor fraction is low. We propose an integrative mechanistic framework in which age-related epigenetic and genomic changes influence both tumor biology and cfDNA composition, with transposable elements acting as a central link between aging and cancer.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"50970"},"PeriodicalIF":3.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889495","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":"CARS1 as a Prognostic Biomarker and Candidate Therapeutic Vulnerability in Hepatocellular Carcinoma: Insights Into Tumor Progression and the Immune Microenvironment.","authors":"Yezhen Tang, Kejun Liu, Zhenyao Tan, Wei Zhao","doi":"10.31083/FBL53642","DOIUrl":"https://doi.org/10.31083/FBL53642","url":null,"abstract":"<p><strong>Background: </strong>Cysteinyl-tRNA synthetase 1 (CARS1) has been included in ferroptosis-related prognostic signatures, but its clinicopathological relevance, cellular functions, and relationship with the immune microenvironment in hepatocellular carcinoma (HCC) remain incompletely characterized.</p><p><strong>Methods: </strong>Transcriptomic and clinical data from The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset were integrated with corresponding data from an institutional HCC tissue cohort of 60 patients. CARS1 expression was evaluated by immunohistochemistry, and immune infiltration was examined using single-sample gene-set enrichment analysis (ssGSEA) and multiplex immunofluorescence, as well as by analyzing public single-cell datasets. The effects of CARS1 depletion were evaluated in MHCC97H and Hep3B cells using Cell Counting Kit-8 (CCK-8) assays, cell-cycle profiling, wound-healing assays, Transwell migration assays, western blotting, and erlotinib-sensitivity assays.</p><p><strong>Results: </strong>CARS1 expression was elevated in HCC and was associated with adverse clinicopathological features and poor overall survival. Quantitative immunohistochemistry confirmed elevated CARS1 protein expression in tumor tissues. CARS1 depletion inhibited cell proliferation, altered cell-cycle distribution, impaired migration, and enhanced <i>in vitro</i> sensitivity to erlotinib. High CARS1 expression was also associated with increased infiltration of Th2-like immune cells.</p><p><strong>Conclusions: </strong>Elevated CARS1 expression is associated with an adverse biological and immune phenotype in HCC. These clinical, histopathological, and loss-of-function findings support further investigation of CARS1 as a prognostic marker and candidate therapeutic target in HCC, although additional mechanistic and <i>in vivo</i> validation is required.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"53642"},"PeriodicalIF":3.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889572","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 Neuroinflammation to Precision Stroke Recovery: A Phase-Specific Immune-Metabolic Framework.","authors":"Pratchaya Kaewkaen","doi":"10.31083/FBL54110","DOIUrl":"https://doi.org/10.31083/FBL54110","url":null,"abstract":"<p><p>Stroke recovery varies markedly among patients and cannot be fully predicted by infarct size, lesion location, or acute treatment success. This variability suggests that recovery is shaped by evolving interactions among neural injury, immune activation, neurovascular integrity, metabolic reserve, and repair-related plasticity. This review proposes a phase-specific immune-metabolic framework for precision stroke recovery. Rather than treating neuroinflammation as a uniformly detrimental process, this review conceptualizes neuroinflammation as a time-dependent biological gate that may either amplify injury or support repair, depending on the phase, cellular context, blood-brain barrier integrity, and systemic metabolic state. In the acute phase, regulated cell death, oxidative stress, inflammasome activation, blood-brain barrier disruption, and proteolytic remodeling contribute to secondary injury and neurovascular instability. During the subacute phase, controlled immune responses may facilitate debris clearance, angiogenesis, synaptic remodeling, and rehabilitation-induced neuroplasticity. In contrast, persistent low-grade inflammation in the chronic phase may impair network reorganization, promote glial reactivity, and contribute to delayed neurodegeneration or poor functional recovery. The available evidence suggests that metabolic and microbiome-related factors are not secondary modifiers but integral components of recovery biology. Nutritional status, sarcopenia, metabolic imbalance, and post-stroke gut dysbiosis may influence immune tone, blood-brain barrier function, microbial metabolite signaling, and neuroplastic potential. These interactions provide a rationale for defining biological recovery endotypes that integrate inflammatory, neurovascular, metabolic, microbiome-related, and plasticity-related signatures. By linking neuroinflammation with immune-metabolic regulation and repair biology, this review reframes stroke recovery as a phase-dependent and biologically stratified process. The framework may support the development of multimodal biomarkers, phase-matched interventions, and patient-stratification strategies for precision stroke recovery trials.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"54110"},"PeriodicalIF":3.1,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889499","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":"Matrix Protective and Anti-Inflammatory <i>In Vitro</i> Potential of Adipose Mesenchymal Stromal Cell-Derived EVs Coupled With Platelet-Derived Fibrin Gel.","authors":"Enrico Ragni, Michela Taiana, Simona Landoni, Federico Valli, Andrea Massimiliano Nebuloni, Paola De Luca, Lorenza Lazzari, Laura de Girolamo, Giuseppe Peretti","doi":"10.31083/FBL54998","DOIUrl":"https://doi.org/10.31083/FBL54998","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The limited intrinsic repair capacity of articular cartilage impairs tissue regeneration in osteoarthritis (OA). Platelet-rich plasma (PRP) fibrin gels offer a viable autologous scaffold for cartilage repair but often promote fibrous tissue rather than native hyaline structures. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) can overcome this limitation by actively promoting hyaline cartilage formation and suppressing matrix degradation. This study describes and validates a protocol for embedding adipose-derived MSC (ASC)-EVs into PRP gels (PRP-EVs) and evaluates the protective efficacy in human pathologic chondrocytes and synoviocytes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;ASC-EVs were isolated via ultracentrifugation, characterized and their microRNA cargo profiled (quantitative reverse-transcription polymerase chain reaction, qRT-PCR). EVs (10 × 10&lt;sup&gt;9&lt;/sup&gt; particles/mL) were loaded into PRP activated with CaCl&lt;sub&gt;2&lt;/sub&gt; to form a fibrin hydrogel. EV incorporation efficiency, 4-week release kinetics, cellular uptake (two-dimensional [2D] and three-dimensional [3D] microfluidic models) and penetration into OA cartilage explants using coherent anti-Stokes Raman scattering/two-photon excited fluorescence CARS/TPEF microscopy were assessed. To evaluate the biological effects of the PRP-EV gel secretome, we analyzed gene expression (qRT-PCR), collagen I/II/X deposition (immunofluorescence), metalloproteinase activity and nitric oxide release (ELISA) in interleukin-1β-stimulated 3D chondrocyte pellets, alongside gene expression in OA patient-derived synoviocytes (qRT-PCR).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The protocol demonstrated high EV encapsulation efficiency (60% ± 8 of the input) in PRP gels and steady kinetics yielding a 20% cumulative release over 4 weeks. Released EVs maintained functional integrity, showing matching 2D/3D uptake in target cells and penetrating to depths exceeding 200 μm within 48 hoursinto OA patients' cartilage explants. In 3D chondrocyte pellets, PRP-EVs significantly downregulated catabolic genes (&lt;i&gt;MMP1&lt;/i&gt;, &lt;i&gt;MMP3&lt;/i&gt;, &lt;i&gt;MMP13&lt;/i&gt;), reducing cumulative matrix metalloproteinase (MMP) enzymatic activity, and blunted nitric oxide production and &lt;i&gt;CCL5&lt;/i&gt; expression. PRP-EVs counteracted PRP-induced fibrosis, significantly increasing the collagen II/I ratio and suppressing hypertrophic collagen X deposition. In synoviocytes, PRP-EVs significantly downregulated key inflammatory, chemotactic, and pain-signaling genes (&lt;i&gt;CCL2&lt;/i&gt;, &lt;i&gt;CXCL8&lt;/i&gt;, &lt;i&gt;CXCL10&lt;/i&gt;, &lt;i&gt;IL-6&lt;/i&gt;, &lt;i&gt;COX2&lt;/i&gt;, &lt;i&gt;NGF&lt;/i&gt;).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This study demonstrates that embedding ASC-EVs within a PRP fibrin hydrogel creates a bioactive delivery system. &lt;i&gt;In vitro&lt;/i&gt;, the secretome released from this composite material successfully counteracts pathological processes in osteoarthritis patient-derived chondrocytes and synoviocytes, reducing matrix degradation and inflammation whil","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"54998"},"PeriodicalIF":3.1,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889023","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":"<i>PDE4DIP</i>-Derived MMG8 Supports Proliferation, Migration, and Tumor Growth in Hepatocellular Carcinoma Models.","authors":"Cong Wang, Chunjing Bian, Tao Luo","doi":"10.31083/FBL54109","DOIUrl":"https://doi.org/10.31083/FBL54109","url":null,"abstract":"<p><strong>Background: </strong><i>PDE4DIP</i> encodes a scaffold protein that has been implicated in compartmentalized signaling and cytoskeletal organization, but the role of its myomegalin variant 8 (MMG8) isoform in hepatocellular carcinoma (HCC) remains unclear. To address this gap, we examined <i>PDE4DIP</i> expression in public HCC datasets and investigated the functional role of MMG8 in HCC models.</p><p><strong>Methods: </strong><i>PDE4DIP</i> expression was analyzed in The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and two Gene Expression Omnibus (GEO) cohorts (GSE14520, GSE36376). MMG8 function was assessed in Huh7 cells using siRNA-mediated knockdown and in Hepa1-6 cells using lentiviral Clustered Regularly Interspaced Short Palindromic Repeats - CRISPR-associated protein 9 (CRISPR-Cas9)-mediated knockout. Cell proliferation in MMG8-KD Huh7 cells and MMG8-KO Hepa1-6 cells was assessed using Cell Counting Kit-8 (CCK-8) assays, while Huh7 cell migration was evaluated using Transwell assays. Tumor growth was assessed using a murine subcutaneous tumor model. Immunohistochemical staining for Ki67 and cleaved caspase-3 was employed to assess tumor cell proliferation and apoptosis-associated changes, respectively. Gene set enrichment analysis was performed in TCGA-LIHC tumors stratified based on <i>PDE4DIP</i> expression.</p><p><strong>Results: </strong><i>PDE4DIP</i> expression differed between tumor and non-tumor tissues across HCC cohorts, although the directionality of this difference was not uniform. MMG8 knockdown in Huh7 cells reduced proliferation and migratory activity. A single-cell-derived MMG8-KO Hepa1-6 clone exhibited reduced proliferation <i>in vitro</i> and formed smaller tumors <i>in vivo</i>, with lower Ki67 positivity but no significant difference in cleaved caspase-3 positivity between groups. In tumors from the TCGA-LIHC cohort, <i>PDE4DIP</i> expression was associated with distinct transcriptional programs. Specifically, <i>PDE4DIP</i>-high tumors presented with positive normalized enrichment score (NES) values for several metabolic pathways, whereas adhesion/extracellular matrix (ECM), cell cycle/proliferation, and translation/ribosome-related pathways exhibited negative NES values.</p><p><strong>Conclusions: </strong>These findings support a functional contribution of MMG8 to proliferative, migratory, and tumor-growth phenotypes in the tested HCC models. Bulk gene-level <i>PDE4DIP</i> expression in human tumors was associated with context-dependent transcriptional states and should not be interpreted as a direct surrogate for MMG8 function.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"54109"},"PeriodicalIF":3.1,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889519","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 an Age-Stratified Perspective: Divergent Adaptive Mechanisms of the Traumatic Brain Injury Repair Network Between Pediatric and Adult Patients.","authors":"Sixun Yu, Liang Pan, Tao Yang, Xin Chen, Yuan Ma, Haifeng Shu","doi":"10.31083/FBL45754","DOIUrl":"https://doi.org/10.31083/FBL45754","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) remains a leading cause of chronic neurological impairment across the lifespan, with significant disparities in clinical recovery trajectories between pediatric and adult patients. Previous research has often been confined to a binary debate over the relative repair capacity of different age groups; however, this paradigm is insufficient for exploring the age-dependent molecular mechanisms of adaptation in depth. This review proposes a \"divergent adaptation\" theoretical framework to systematically analyze age-dependent differences in the brain-derived neurotrophic factor (BDNF)-miRNA network and its microenvironmental regulation-including cerebrospinal fluid dynamics and the gut-brain axis-during TBI repair. In the pediatric brain, repair strategies primarily leverage developmental plasticity, characterized by elevated BDNF/insulin-like growth factor-1 (IGF-1) expression and the active involvement of neurogenesis-promoting miRNAs such as miR-124, which facilitate neural circuit reorganization. However, this reparative process also entails risks, including aberrant circuit formation and vascular fragility. In contrast, the adult brain employs repair strategies focused on maintaining network stability: BDNF/TrkB signaling shifts toward localized repair, while miR-129-mediated inhibition of IGF-1 and epigenetic silencing mechanisms (e.g., BDNF promoter hypermethylation) constrain regenerative capacity and favor gliotic scar formation. Furthermore, cross-system mechanisms-such as the unique cerebrospinal fluid dynamics in children and the \"developmental window effect\" of the gut-brain axis-may contribute to distinct injury response patterns across ages. From a clinical translational perspective, we emphasize that intervention strategies must be precisely tailored according to age-specific mechanisms. For pediatric patients, potential approaches include exosome-mediated delivery of neurogenic miRNAs (e.g., miR-133b) and IGF-1 potentiation therapies. For adults, more suitable strategies may involve electroacupuncture-mediated modulation of the BDNF-miRNA axis or CRISPR/dCas9-based reversal of epigenetic silencing. Additionally, natural compounds such as curcumin, which confer synergistic anti-inflammatory effects via the BDNF/miRNA network, could represent a universal therapeutic strategy applicable across age groups. This field faces several limitations, however, including a scarcity of high-quality pediatric TBI data, a translational gap between animal models and clinical reality, and an incomplete understanding of cross-system mechanisms. Future studies should establish developmentally staged research systems and integrate multi-omics technologies to advance precision neuroregenerative strategies.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"45754"},"PeriodicalIF":3.1,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889528","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":"PCSK9 as a Key Gene of Metastasis in Lung Adenocarcinoma: A Multi-omics and Experimental Validation Study.","authors":"Dan Zong, Dejun Wang, Luxi Qian, Ning Jiang, Lijun Zhao, Cheng Chen, Xia He","doi":"10.31083/FBL49685","DOIUrl":"https://doi.org/10.31083/FBL49685","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) is the most common form of lung cancer. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is abnormally expressed in various tumor tissues and is associated with malignant phenotypes. However, the clinical significance, function, and mechanism of LUAD invasion and metastasis remain unclear.</p><p><strong>Methods: </strong>We retrospectively enrolled 100 patients with LUAD in this study. Initially, qRT-PCR was performed to detect PCSK9 levels in clinical tissues. Subsequently, bioinformatics analysis of scRNA-seq and The Cancer Genome Atlas Program (TCGA) datasets was performed to predict the role of PCSK9 in tumor cell malignancy and its potential downstream pathways. These predictions were validated experimentally using the CCK-8 assay, TUNEL staining, wound healing, transwell invasion assay, and an <i>in vivo</i> lung metastasis model. Finally, Western blotting and an AKT inhibitor (MK2206) were used to verify the underlying mechanism.</p><p><strong>Results: </strong>PCSK9 was significantly upregulated in LUAD tissues compared to paracancerous tissues and was associated with poorer OS and DFS. Bioinformatics analysis of scRNA-seq data and TCGA analysis predicted that PCSK9 is highly enriched in tumor cells and is involved in EMT, and that the PI3K/AKT pathway plays a significant role in LUAD development. Experiments confirmed that PCSK9 markedly promoted LUAD cell proliferation, migration, and invasion <i>in vitro</i> and lung metastasis <i>in vivo</i>. PCSK9 overexpression significantly upregulated p-AKT, p-PI3K, and p-mTOR levels. Furthermore, the AKT inhibitor, MK2206, reversed the promoting effects of PCSK9.</p><p><strong>Conclusions: </strong>PCSK9 expression is associated with the prognosis and diagnosis of LUAD. This molecule activates the PI3K/AKT signaling pathway, thereby driving invasion, metastasis, and proliferation in LUAD.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"49685"},"PeriodicalIF":3.1,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889573","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":"EIF4EBP1 in Breast Cancer: Translational Control, Regulatory Networks, and Therapeutic Frontiers.","authors":"Weijia Liu, Lili Hou, Dandan Tang, Haiyu Mou, Weijie Wang, Song-Bai Liu, Xiaohua Li","doi":"10.31083/FBL45484","DOIUrl":"https://doi.org/10.31083/FBL45484","url":null,"abstract":"<p><p>Eukaryotic initiation factor 4E-binding protein 1 (EIF4EBP1/4E-BP1) is a pivotal translational regulator with context-dependent roles in breast cancer pathogenesis. Its phosphorylation status, dynamically controlled by mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), and AMP-activated protein kinase (AMPK) signaling, dictates a dualistic function: hypophosphorylated EIF4EBP1 suppresses oncogenesis by sequestering eIF4E and inhibiting cap-dependent translation of pro-tumorigenic mRNAs (e.g., cyclin D1 and c-MYC), while hyperphosphorylation promotes tumor progression and therapeutic resistance. EIF4EBP1 amplification (8p11-p12) is correlated with endocrine resistance and poor prognosis. EIF4EBP1 modulates cell cycle checkpoints, metabolic adaptation under stress, and resistance to cyclin-dependent kinase (CDK) 4 and 6 inhibitors and rapalogs via feedback loops (e.g., SGK3/Akt reactivation). Emerging therapeutic strategies, such as ATP-competitive mTOR inhibitors, bisteric compounds, and agents targeting polyamine metabolism or upstream kinases, exploit the dynamics of EIF4EBP1 phosphorylation. As a biomarker, phosphorylated EIF4EBP1 levels predict tumor aggressiveness and treatment failure, positioning it as a critical node for precision oncology. Future research must address spatial heterogeneity and leverage multi-omics/AI-driven approaches.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"45484"},"PeriodicalIF":3.1,"publicationDate":"2026-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889543","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}