Frontiers in bioscience (Landmark edition)最新文献

{"title":"Role of AMPK Signaling in the Neuroprotective Effects of Trehalose in Mice With a Pharmacological Model of Alzheimer's Disease.","authors":"Alexander B Pupyshev, Marina V Ovsyukova, Anna A Akopyan, Michael V Tenditnik, Tatiana A Korolenko, Nina I Dubrovina, Maria A Tikhonova","doi":"10.31083/FBL53657","DOIUrl":"https://doi.org/10.31083/FBL53657","url":null,"abstract":"<p><strong>Background: </strong>Trehalose (TRE) has demonstrated neuroprotective potential in models of Alzheimer's disease (AD)-like pathology and has been shown to activate AMP-activated protein kinase (AMPK) and induce autophagy in hepatocytes. The molecular mechanisms underlying the neuroprotective effects of TRE in the brain, including the involvement of AMPK signaling and autophagy, remain unclear.</p><p><strong>Methods: </strong>AD was modeled in C57BL/6 mice by intracerebroventricular administration of the amyloid-β (Aβ) fragment Aβ(25-35). The effects of TRE treatment (a 3% water solution in drinking water for 20 days) on AD-like pathology in the brain (frontal cortex, amygdala, and hippocampus) were assessed by immunohistochemical analysis, while cognitive function was evaluated using the passive avoidance test. AMPK activation was assessed by measuring AMPK (p-AMPK) levels in the brain and by evaluating the effects of its inhibitor dorsomorphin (DM; 10 mg/kg, i.p., 20 days, every other day for 20 days).</p><p><strong>Results: </strong>Aβ-treated mice exhibited markedly increased Aβ levels and neuroinflammatory responses in the brain, whereas levels of the autophagy marker LC3-II and p-AMPK were moderately reduced. TRE markedly reduced Aβ accumulation and neuroinflammation and restored cognitive performance to levels comparable to those of the Control group; it also increased LC3-II immunoreactivity and p-AMPK levels in the hippocampus and amygdala. DM did not abolish the neuroprotective effects of TRE but moderately inhibited AMPK in the hippocampus.</p><p><strong>Conclusions: </strong>Marked changes in brain Aβ levels and cognitive performance were not associated with either p-AMPK or autophagy marker levels, suggesting that additional mechanisms contribute to the neuroprotective effects of TRE in AD. Markers of autophagy initiation and AMPK activity responded similarly to AD modeling and TRE treatment and were positively correlated in the hippocampus, suggesting a role for AMPK in the regulation of TRE-induced hippocampal autophagy.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"53657"},"PeriodicalIF":3.1,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889512","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":"Mechanism-Targeted Therapeutic Strategies for Traumatic Brain Injury: From Molecular Pathways to Functional Recovery.","authors":"Ana Costa, Steven Davidson, Emiliya Rakhamimova, Benjamin Bartula, Sofia Geralemou, Weidong Wang, Sergio D Bergese","doi":"10.31083/FBL48402","DOIUrl":"https://doi.org/10.31083/FBL48402","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is characterized by a \"translational paradox\", where robust preclinical successes rarely achieve clinical efficacy. This review provides a critical appraisal of emerging therapeutics, moving beyond traditional silos to propose a unified, stage-dependent roadmap for neurorestoration. Reflecting on translational insights from past trials, specifically the limitations of standardized timing and phenotypic heterogeneity, we introduce the \"Temporal Precision Medicine\" framework. Central to this synthesis is the Dual-Axis Theory, which posits that successful emerging modalities, including repurposed agents such as glibenclamide, amantadine, and statins, alongside cell-free biologics and neuromodulation, converge on two shared pathological targets: the Inflammatory Axis (M1-to-M2 microglial polarization) and the Metabolic Axis (restoration of mitochondrial bioenergetics). We operationalize these biological insights into a Triple-Axis Framework, a dynamic clinical roadmap that aligns stage-dependent interventions with phase-specific biomarkers and pathological mechanisms. By integrating these biological signals with bioengineered delivery systems and artificial intelligence (AI)-driven precision phenotyping, the field can transition from acute neuroprotection toward genuine circuit-level regeneration. We conclude with a blueprint for the next generation of TBI trials, emphasizing biomarker-based stratification and multidimensional endpoints to bridge the translational gap.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"48402"},"PeriodicalIF":3.1,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889412","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":"Multimodal Analysis Reveals Aberrant Expression of SUMO2 and Its Significant Association With Key Mechanisms of Metabolic Pathways in Hepatocellular Carcinoma.","authors":"Yulong Deng, Beibei Huang, Yuxing Tang, Qinyan Su, Hongquan Liu, Hongbo Mo, Huanhuan Tang, Kunhua Xiong, Shipei He, Yiwu Dang, Gang Chen, Minhua Rong","doi":"10.31083/FBL52385","DOIUrl":"https://doi.org/10.31083/FBL52385","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. However, the role of small ubiquitin-like modifier 2 (SUMO2), a core member of the small ubiquitin-like modifier (SUMO) family, regarding its expression patterns and metabolism-related functions in HCC remains inadequately understood.</p><p><strong>Methods: </strong>A multidimensional analytical framework was applied, integrating immunohistochemistry (153 HCC vs. 21 non-HCC samples), proteomics (159 paired samples), bulk transcriptomics (3240 HCC vs. 2267 non-HCC samples), single-cell RNA sequencing (RNA-seq) (10 HCC vs. 8 non-HCC samples), spatial transcriptomics, and external CRISPR/Cas9 functional genomics data. Systematic analyses included standardized mean difference (SMD), pathway enrichment, pseudotime trajectory inference, <i>in silico</i> knockout, cell-cell communication, metabolic flux scoring, immune infiltration, clinical correlation, drug sensitivity prediction, and molecular docking.</p><p><strong>Results: </strong>At the protein level, immunohistochemistry (nuclear positivity) and external proteomic data collectively demonstrated consistent SUMO2 overexpression in HCC. Consistent upregulation was also observed at the mRNA level across large-scale cohorts. Single-cell RNA-seq and spatial transcriptomics localized SUMO2 enrichment to malignant hepatocytes and tumor-dominant regions. CRISPR-mediated SUMO2 knockout suppressed proliferation in multiple HCC cell lines. Mechanistically, high SUMO2 expression was significantly associated with metabolic reprogramming involving glycolysis/gluconeogenesis, pyruvate metabolism, and the tricarboxylic acid cycle. SUMO2-high malignant hepatocyte subpopulations exhibited enhanced activity of the macrophage migration inhibitory factor signaling axis and enhanced iron-sensor interactions. Further, the immune infiltration analysis revealed a negative correlation between SUMO2 expression and M1 macrophages and a positive correlation between follicular helper T cells and regulatory T cells. Clinically, elevated SUMO2 levels were found to be associated with adverse prognostic features. Furthermore, high SUMO2 expression was associated with increased sensitivity to dasatinib, and molecular docking simulations predicted potential binding between SUMO2 and dasatinib, with a Vina score of -8.5 kcal/mol.</p><p><strong>Conclusions: </strong>SUMO2 is aberrantly expressed at the protein, mRNA, single-cell, and spatial transcriptomic levels in HCC and is significantly associated with metabolic reprogramming and altered migration inhibitory factor (MIF)-mediated intercellular communication, suggesting its potential as a novel biomarker for diagnosis and treatment.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"52385"},"PeriodicalIF":3.1,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889523","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":"Membrane Potential Hyperpolarization Controls the Osteogenic Differentiation of Human Dental Follicle Stem Cells by Increasing Intracellular Ca²⁺ Levels.","authors":"Yidan Yang, Weijia Du, Dan Yang, Yuyang Luo, Qian Zhou, Dongchuan Zuo, Jin Zeng","doi":"10.31083/FBL53140","DOIUrl":"https://doi.org/10.31083/FBL53140","url":null,"abstract":"<p><strong>Background: </strong>Kir2.1 channels are responsible for membrane hyperpolarization of many cell types. While these Kir2.1 channels are known to be necessary for proper bone development and play a critical role in osteogenesis, the underlying mechanisms remain poorly understood. Here, we examined the effect of Kir2.1-mediated membrane hyperpolarization on the osteogenic differentiation of human dental follicle stem cells (hDFCs), a type of mesenchymal stem cell (MSC), and explored the underlying mechanisms.</p><p><strong>Methods: </strong>Levels of Kir2.1 and osteogenic marker expression were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Alkaline phosphatase (ALP) and Alizarin red staining were employed to evaluate ALP enzymatic activity and mineralized nodule formation, respectively. Intracellular Ca²⁺ levels were measured using fluorescent Ca²⁺ indicators with Ca²⁺ imaging.</p><p><strong>Results: </strong>Reversal of membrane hyperpolarization via modulation of extracellular K⁺ concentration ([K⁺]_e) was shown to suppress osteogenic differentiation of hDFCs, whereas the induction of membrane hyperpolarization through the opening of ATP-sensitive K⁺ channels had the opposite effect, enhancing hDFC osteogenesis. Kir2.1 channel expression was upregulated during the osteogenic differentiation of hDFCs. Inhibition of Kir2.1 using short hairpin RNA (shRNA) or a pharmacological inhibitor suppressed osteogenic differentiation. Hyperpolarizing the membrane by decreasing [K⁺]_e led to the elevation of intracellular Ca²⁺ levels, whereas this effect was eliminated by the removal of extracellular Ca²⁺, Kir2.1 inhibition, or treatment with La³⁺, a store-operated Ca²⁺ channel (SOC) blocker.</p><p><strong>Conclusions: </strong>Our findings indicate that membrane hyperpolarization promotes osteogenic differentiation of hDFCs by increasing intracellular Ca²⁺ levels and that the Kir2.1 and SOC channels play important roles in this process.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"53140"},"PeriodicalIF":3.1,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889427","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":"Reverse Network Pharmacology-Based Identification of 20-Hydroxyecdysone and Its Inhibition of Glioblastoma Malignant Phenotypes Through the PI3K/AKT Pathway.","authors":"Jinhui Zhang, Chao Wei, Dongyan Wang, Renmi He, Xiangdan Xiao, Jianwei Xu, Junhou Lu","doi":"10.31083/FBL52978","DOIUrl":"https://doi.org/10.31083/FBL52978","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma is the most aggressive primary malignant brain tumor of the central nervous system and remains difficult to treat because of rapid progression, diffuse invasion, and frequent recurrence. This study aimed to identify a potential natural compound against glioblastoma using a reverse network pharmacology strategy and to investigate its anti-glioma effects and underlying mechanism.</p><p><strong>Methods: </strong>Glioblastoma-related targets were collected from public disease databases and integrated with differentially expressed genes from a public transcriptomic dataset to identify intersecting targets. Protein-protein interaction analysis, hub target screening, functional enrichment analysis, and reverse network pharmacology were performed to identify candidate compounds. Molecular docking and 100-ns molecular dynamics simulations were used to assess interactions between 20-hydroxyecdysone and pathway-related targets. Cell viability, colony formation, apoptosis, migration, and protein expression were examined in U251 and U87 glioma cells. Statistical differences were analyzed using a paired Student's <i>t</i>-test for two-group comparisons or one-way analysis of variance (ANOVA) followed by Dunnett's multiple-comparisons test for multi-group comparisons, as appropriate.</p><p><strong>Results: </strong>A total of 136 intersecting targets and 18 hub targets were identified. Functional enrichment analysis indicated that the phosphatidylinositol 3-kinase/protein kinase B signaling pathway was one of the key enriched pathways. Reverse network pharmacology identified 20-hydroxyecdysone as a candidate compound. Molecular docking showed relatively strong binding of 20-hydroxyecdysone to epidermal growth factor receptor, fms-related receptor tyrosine kinase 1, and integrin subunit alpha 5, and molecular dynamics simulations supported the stability of these complexes. <i>In vitro</i> experiments showed that 20-hydroxyecdysone inhibited cell viability, clonogenicity, and migration, while promoting apoptosis. It also reduced the phosphorylation levels of phosphatidylinositol 3-kinase, protein kinase B, and glycogen synthase kinase 3 beta at Ser9 without markedly altering total protein expression.</p><p><strong>Conclusion: </strong>Treatment with 20-Hydroxyecdysone showed anti-glioma activity <i>in vitro</i> and may exert its effects, at least in part, through suppression of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway. These findings support its further evaluation as a potential therapeutic candidate for glioblastoma.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"52978"},"PeriodicalIF":3.1,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889535","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":"Reversible vs. Irreversible Neuronal Injury in Brain Ischemia: Role of the Mitochondrial-Synaptic Axis.","authors":"Ki-Yeon Yoo, Bo Hyun Jung, Ji Hyeon Ahn, Moo-Ho Won","doi":"10.31083/FBL49412","DOIUrl":"https://doi.org/10.31083/FBL49412","url":null,"abstract":"<p><p>Ischemia-reperfusion (I/R) injury triggers a rapid and self-amplifying cascade of mitochondrial dysfunction, synaptic instability, and neuroinflammation that ultimately determines neuronal survival and functional recovery. Early bioenergetic collapse-driven by mitochondrial depolarization, Reactive oxygen species (ROS) overproduction, and impaired mitophagy-initiates excitotoxic signaling and calpain-mediated structural degradation at vulnerable synapses. These events converge with microglial and astrocytic activation to exacerbate cytokine release, blood-brain barrier (BBB) disruption, and delayed neuronal injury. Therapeutic strategies targeting this axis show considerable promise. Mitochondria-directed interventions-including mitophagy modulation, Dynamin-related protein 1 (Drp1) inhibition, antioxidant nanocarriers, and emerging mitochondrial transplantation-restore Adenosine triphosphate (ATP) production, stabilize membrane potential, and prevent downstream excitotoxic injury. Synaptic protection via N-methyl-D-aspartate (NMDA)/postsynaptic density protein-95 (PSD-95) uncoupling, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor stabilization, and calpain inhibition preserves dendritic architecture and neurotransmission. Modulation of inflammatory pathways, particularly Interleukin-1β (IL-1β), Tumor necrosis factor-α (TNF-α), and Interleukin-6 (IL-6) signaling, as well as cell-specific microglial and astrocytic reprogramming, further attenuates secondary degeneration. Gene- and RNA-based therapies, nanoparticles engineered for BBB penetration, and extracellular vesicle-mediated delivery systems represent additional advanced platforms moving toward clinical translation. Despite substantial progress, challenges remain, including timing constraints, region-specific vulnerability (e.g., CA1 vs. CA3), limited BBB permeability, and species differences in mitochondrial dynamics and glial responses. Integrative multimodal strategies-combining mitochondrial repair, synaptic stabilization, and immunomodulation-along with advanced imaging, spatial transcriptomics, and patient-derived organoids, may accelerate the development of precision therapies for I/R injury. This review synthesizes mechanistic and translational evidence demonstrating that the mitochondria-synapse-inflammation axis forms a unified pathological framework across experimental and clinical I/R settings, including transient focal ischemia, global ischemia following cardiac arrest (CA), and reperfusion after thrombolysis or thrombectomy.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"49412"},"PeriodicalIF":3.1,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889565","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":"Endophilin Proteins in Membrane Dynamics, Neurodegeneration, Cancer, and Cardiovascular Disease.","authors":"Xiaoyun Liu, Shuxian Fan, Xuediao Pan, Huimin Pang, Wenwei Su, Song Liu","doi":"10.31083/FBL49204","DOIUrl":"https://doi.org/10.31083/FBL49204","url":null,"abstract":"<p><p>The endophilin protein family comprises a group of evolutionarily highly conserved Bin-Amphiphysin-Rvs (BAR) domain proteins that play key roles in cell membrane morphogenesis, endocytic trafficking, and organelle dynamics. The human endophilin family includes five main members, encoded by the genes <i>SH3GL2</i> (endophilin A1), <i>SH3GL1</i> (endophilin A2), <i>SH3GL3</i> (endophilin A3), <i>SH3GLB1</i> (endophilin B1), and <i>SH3GLB2</i> (endophilin B2). Notably, <i>SH3GLB1</i> gives rise to functionally distinct splice variants, including the ubiquitously expressed B1a and the neuron-enriched B1b/c, which play critical, opposing roles in conditions such as Alzheimer disease (AD). These isoforms perform distinct, often opposing functions in disease pathogenesis via specific molecular mechanisms. For instance, endophilin A1 acts as a tumor suppressor; its gene, <i>SH3GL2</i>, is frequently deleted or downregulated in cancers such as non-small cell lung cancer, and its loss promotes tumor progression by sustaining epidermal growth factor receptor (EGFR) signaling. Conversely, endophilin A2 drives cancer metastasis. In AD, endophilin A1 expression is significantly elevated, exacerbating synaptic dysfunction, while neuron-specific endophilin B1 isoforms are decreased, worsening amyloid pathology. The regulation of endophilins involves intricate networks, including post-transcriptional control by microRNAs (e.g., miR-330 targeting <i>SH3GL2</i> in glioblastoma) and post-translational modifications. This review provides a comprehensive overview of the structural characteristics and regulation of expression and activity. It delineates the molecular mechanisms by which their dysfunction contributes to disease pathogenesis, aiming to provide new insights into these multifaceted proteins in health and disease.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"49204"},"PeriodicalIF":3.1,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889558","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":"Dexmedetomidine Mitigates Sepsis-Associated Lung Injury by Suppressing Macrophage Ferroptosis via the Nrf2/HO-1 Signaling Pathway.","authors":"Bei Ma, Renjie Luo, Gang Kuang, Jian Liu, Xi Chen, Fang Xu, Yisi Zhao","doi":"10.31083/FBL53058","DOIUrl":"https://doi.org/10.31083/FBL53058","url":null,"abstract":"<p><strong>Background: </strong>To investigate the protective role of dexmedetomidine (DEX) in sepsis-associated acute lung injury through the regulation of macrophage ferroptosis.</p><p><strong>Methods: </strong><i>In silico</i> screening of GeneCards and FerrDb Vv3 databases was performed to identify ferroptosis-related candidate genes modulated by dexmedetomidineDEX, lung injury, and macrophage activity, prioritizing nuclear factor erythroid 2-related factor 2 (<i>Nrf2</i>)/<i>Nfe2l2</i> for subsequent experimental validation. A murine cecal ligation and puncture model of acute lung injury (ALI) and lipopolysaccharide-stimulated macrophages were established and subjected to treatment with DEX and/or the Nrf2 inhibitor ML385. Glutathione peroxidase 4 (GPX4), Nrf2, and heme oxygenase-1 (HO-1) protein levels were analyzed using western blotting. Ferroptosis and oxidative stress markers (superoxide dismutase [SOD], glutathione [GSH], iron content, reactive oxygen species [ROS], malondialdehyde [MDA]) were measured. Samples of fresh lung tissue were observed by electron microscopy. Macrophage phenotypes and tumor necrosis factor alpha (TNF-α) expression were assessed. Macrophage-conditioned medium was used to culture non-small cell adenocarcinoma epithelial cells (A549), and cell migration was evaluated. Proliferation-related proteins (matrix metalloprotease 9 [MMP-9] and Snail-1), key tight junction proteins (zonula occludens-1 [ZO-1] and occludin) and the apoptotic status were also analyzed.</p><p><strong>Results: </strong>DEX significantly reduced ROS, iron content, and MDA levels while concomitantly increasing SOD activity and GSH content in both ALI model mice and LPS-treated macrophages. DEX inhibited pro-inflammatory M1 macrophage polarization with a concomitant decrease in TNF-α release through Nrf2-dependent mechanisms. DEX was found to mitigate inflammatory microenvironment-induced macrophage ferroptosis through activation of Nrf2 signaling, thereby reducing damage in A549 cells. This effect may be linked to the regulation of macrophage inflammatory phenotypes.</p><p><strong>Conclusions: </strong>DEX improved sepsis-associated ALI by inhibiting macrophage ferroptosis and polarization toward the M1 type by activation of the Nrf2/HO-1 pathway.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"53058"},"PeriodicalIF":3.1,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889482","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":"Beauvericin Exerts Antitumor Effects on Multiple Myeloma by Disrupting the USP9X-Bcl-2 Interaction to Promote Bcl-2 Degradation.","authors":"Rui Jin, Runfeng Ni, Ning Ding, Yuchen Tao, Shuyang Cai, Yirong Shi, Milin Liu, Yirong Chen, Letian Yu, Jiahui Lu","doi":"10.31083/FBL51975","DOIUrl":"https://doi.org/10.31083/FBL51975","url":null,"abstract":"<p><strong>Background: </strong>Beauvericin is a cyclic hexadepsipeptide derived from <i>Bombyx batryticatus</i>. It is known as Jiangcan in traditional Chinese medicine and has diverse pharmacological properties, including antitumor, antiviral, insecticidal, and antibacterial effects. However, its specific mechanisms against multiple myeloma (MM) are not fully understood. The aim of this study was to elucidate the mechanism of beauvericin in MM.</p><p><strong>Methods: </strong>This study utilized the mouse Sp2/0 cell line, the human U266 cell line, and a subcutaneous tumor allograft model in C57BL/6J mice. Flow cytometry was employed to evaluate apoptosis, and the Cell Counting Kit-8 (CCK-8) assay was used to measure cellular viability. Network pharmacology was employed for target prediction, followed by molecular docking analyses to confirm drug-target interactions. The protein expression levels of Ubiquitin-Specific Protease 9X (USP9X) and Bcl-2 were assessed by Western blotting following USP9X knockdown. Additionally, co-immunoprecipitation assays were performed to evaluate whether beauvericin modulates the Bcl-2/USP9X interaction and affects Bcl-2 ubiquitination. The antitumor effects of beauvericin were further evaluated through <i>in vivo</i> experiments.</p><p><strong>Results: </strong>Network pharmacology analysis identified 82 MM-related target genes for beauvericin. These included key targets such as Caspase-3, Bcl-2, Matrix metallopeptidase 9 (MMP9), and Caspase-8, which may contribute to the anti-MM effects of beauvericin. Molecular docking revealed strong affinity and stability between beauvericin and Bcl-2. <i>In vitro</i> experiments confirmed that beauvericin inhibits MM cell proliferation, promotes apoptosis, and enhances Bcl-2 ubiquitination and degradation by disrupting the interaction between the deubiquitinating enzyme USP9X and Bcl-2. <i>In vivo</i> studies demonstrated that beauvericin treatment suppressed the growth of subcutaneous MM tumors C57BL/6J mice.</p><p><strong>Conclusion: </strong>Beauvericin may exert its anti-MM effects by disrupting the USP9X-Bcl-2 interaction, thereby promoting Bcl-2 ubiquitination and degradation, and inducing cell apoptosis in MM cells.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"51975"},"PeriodicalIF":3.1,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889527","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":"Physiological Hypoxia as a Potent Tool for Directed Modification of the Extracellular Matrix of Multipotent Mesenchymal Stromal Cells <i>In Vitro</i>.","authors":"Diana Matveeva, Aleksandra Gornostaeva, Elena Andreeva, Ludmila Buravkova","doi":"10.31083/FBL52962","DOIUrl":"https://doi.org/10.31083/FBL52962","url":null,"abstract":"<p><strong>Background: </strong>Multipotent mesenchymal stromal cells (MSCs) are widely used in regenerative medicine. Their decellularized extracellular matrix (dECM) has emerged as a key bioactive substrate for tissue engineering. The properties of MSC-derived dECM depend on cell culture conditions. Physiological hypoxia mimics the native MSC milieu and represents a promising preconditioning strategy. This study aimed to evaluate the structural and mechanical properties of dECM derived from MSCs cultured under different oxygen levels and to assess the phenotype of MSCs recellularized on these matrices.</p><p><strong>Methods: </strong>Human adipose-derived MSCs were permanently expanded under 20% or 5% O₂ to obtain 20-dECM and 5-dECM. Matrix architecture was visualized using scanning electron microscopy and quantitative phase contrast. Stiffness of dECM was measured by atomic force microscopy. MSCs were recellularized on dECM and cultured under 20% O₂ for 72 hours. The assessment of cell morphology, cytoskeletal organization, nuclear translocation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), integrin expression, levels of reactive oxygen species (ROS), and cell cycle analysis were assessed using confocal microscopy and flow cytometry.</p><p><strong>Results: </strong>In comparison with 20-dECM, 5-dECM demonstrated significant alignment of fibrillar bundles and a 1.6-fold increase in stiffness (<i>p</i> < 0.05). Reseeded MSCs on 5-dECM have acquired a spindle-shaped, aligned morphology, whereas cells on 20-dECM displayed a rounded morphology with multiple processes. The YAP and TAZ nuclear-to-cytoplasmic ratio was significantly lower on both dECM compared with uncoated surfaces (<i>p</i> < 0.0001). Total fluorescence intensity of YAP and TAZ per cell revealed divergent patterns on 5-dECM vs 20-dECM: YAP levels were increased, whereas TAZ levels were decreased. The expression of integrin α2 and α6 was higher (<i>p</i> < 0.01), while the expression of integrin α1 and intercellular adhesion molecule 1 (ICAM-1) was lower on both dECM vs control (<i>p</i> < 0.05). Intracellular ROS levels were reduced twofold on dECM (<i>p</i> < 0.01). The proportion of MSCs in the G2/M phase and the increase in cell number were more significant on dECM compared with uncoated plastic.</p><p><strong>Conclusions: </strong>Hypoxia-derived dECM exhibits increased anisotropy and stiffness, promoting MSC alignment and cytoskeleton organization, integrin expression, altering the subcellular localization of YAP and TAZ and reducing ROS levels. Thus, it may represent a promising, effective bioactive scaffold for MSC expansion.</p>","PeriodicalId":73069,"journal":{"name":"Frontiers in bioscience (Landmark edition)","volume":"31 8","pages":"52962"},"PeriodicalIF":3.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148889487","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}