Research最新文献

Understanding cellular dynamics requires real-time high-resolution imaging. Recent advancements in imaging technologies have provided unprecedented spatial and temporal resolutions, enabling the precise in situ monitoring of live-cell behavior. This review covers 4 advanced imaging modalities: stimulated emission depletion microscopy, structured illumination microscopy, single-molecule localization microscopy, and Raman spectroscopy. We summarize the principles, applications, advantages, and limitations of these methods, highlighting their significance for high-precision spatiotemporal monitoring of cellular structures and biochemical activities. These tools enable precise tracking of molecular interactions and analysis of cellular dynamics at the nanoscale, which is critical for understanding cellular physiology. The integration of these technologies into biomedical research has markedly enhanced our ability to observe live-cell processes, such as division, migration, differentiation, and signaling. The development and application of these high-precision imaging technologies hold substantial promise for improving disease diagnosis, therapeutic strategies, and drug discovery.

Brain metastasis (BrM) is a common occurrence in lung cancer and substantially worsens the prognosis due to the blood-brain barrier (BBB), which restricts drug entry into the brain. Here, we found that exosomes secreted by lung cancer cells that had acquired epidermal growth factor receptor tyrosine kinase inhibitor resistance and undergone epithelial-mesenchymal transition (osimertinib- and WZ4002-resistant H1975) exhibited enhanced brain-specific distribution and a concomitant increase in BrM compared with exosomes from parental H1975 cells. To identify exosomal mediators of this phenotype, liquid chromatography-tandem mass spectrometry-based proteomic analysis was performed. Exosomes derived from resistant cell lines exhibited distinct protein profiles relative to parental cells, with 744 exosomal proteins significantly altered (fold change ≥ 2; P ≤ 0.05). Prioritization of membrane proteins and ligand-receptor interaction analysis identified ITGAV (integrin αV), ITGB3 (intergrin β3), and L1CAM (L1 cell adhesion molecule) as candidates interacting with brain-specific ligands, including neural cell adhesion molecule 1 (NCAM1) and contactin 2. Validation of exosomal association by Western blotting identified ITGB3 and L1CAM as final candidates. Subsequent functional modulation studies demonstrated that exosomal L1CAM plays a dominant role in brain distribution and metastatic progression. Exosomal L1CAM increased BBB permeability by disrupting endothelial tight-junction integrity both in vitro and in vivo. This effect was associated with the involvement of NCAM1 on BBB endothelial cells, as suggested by an exosomal L1CAM masking experiment. Clinically, exosomal L1CAM demonstrated diagnostic potential for BrM (area under the curve [AUC] = 0.80), and a combined exosomal L1CAM/ITGB3 panel significantly improved diagnostic accuracy (AUC = 0.98). Collectively, these findings identify exosomal L1CAM as a key regulator of brain-specific metastasis and support the clinical utility of the L1CAM/ITGB3 panel as a noninvasive biomarker for BrM in lung cancer.

Direct generation (DG) technologies-comprising dielectric elastomer generators (DEGs) and dielectric fluid generators (DFGs)-offer a promising paradigm for ocean wave energy conversion by integrating transduction mechanisms directly into wave-responsive materials. This assessment provides a comprehensive analysis of DG systems, outlining their working principles, recent material innovations, and comparative performance in harsh marine environments. We examine advancements in dielectric materials, including silicone-based and emerging nonsilicone elastomers, and discuss their influence on energy density, electromechanical efficiency, and environmental resilience. Comparative assessments highlight the advantages of DFGs in long-term durability and energy conversion under complex wave dynamics, while DEGs remain competitive due to their mechanical flexibility and scalable fabrication. The review concludes with a discussion of hybrid system integration, challenges in large-scale deployment, and a roadmap toward commercialization. By synthesizing current research trajectories, this article aims to accelerate the transition from laboratory-scale prototypes to deployable, cost-effective ocean energy harvesting solutions.

Hypoxia promotes oral squamous cell carcinoma (OSCC) progression by disrupting redox equilibrium; however, how tumor cells precisely calibrate prosurvival reactive oxygen species levels remains unclear. This study identifies a hypoxia-inducible signaling axis centered on the posttranslational crotonylation of the molecular chaperone heat shock protein 90 alpha family class B member 1 (HSP90AB1), which stabilizes thioredoxin (TXN) to constrain oxidative stress. Hypoxia triggered the hypoxia-inducible factor-1α (HIF-1α)-dependent transcriptional up-regulation of acyl-CoA oxidase 1 (ACOX1), increasing the level of crotonyl-CoA to drive the site-specific crotonylation of HSP90AB1 at lysine 265 (K265cr). Molecular dynamics simulations revealed that K265 crotonylation induced the conformational compaction of HSP90AB1, strengthening its interaction with TXN and enhancing its stability. This chaperone-client axis effectively buffers reactive oxygen species to protumorigenic thresholds, promoting proliferation and conferring cisplatin resistance. Clinically, HIF-1α/ACOX1/HSP90AB1 K265cr/TXN pathway activation is correlated with advanced disease and reduced survival in OSCC patients. Crucially, the HSP90AB1 K265R mutation or pharmacological inhibition of ACOX1 (10,12-tricosadiynoic acid) or TXN (1-methyl-propyl 2-imidazolyl disulfide, PX-12) synergizes with cisplatin to suppress tumor growth in vivo by disrupting redox adaptation. These findings reveal that crotonylation is a hypoxia-sensitive rheostat for TXN-mediated redox control, suggesting that the ACOX1-HSP90AB1-TXN axis is a therapeutic vulnerability in therapy-resistant OSCC.

Achieving both selective pollutant degradation and real-time detection within a single micromotor system remains challenging for environmental monitoring. To address this limitation, we engineered gold-nanostar-decorated, molecularly imprinted BiVO₄ micromotors that combine simultaneous capture, photocatalytic degradation, and in situ detection of pollutants via surface-enhanced Raman spectroscopy (SERS). Plasmonic gold nanostars provide strong SERS enhancement for real-time tracking of pollutant degradation, while micromotors maintain autonomous propulsion under visible light irradiation. Surface molecular imprinting ensures selective recognition of rhodamine 6G and synergistically improves both photocatalytic and sensing performance. This multifunctional design establishes an all-in-one micromotor platform that bridges environmental remediation and on-board monitoring, opening opportunities for advanced water treatment technologies.

Hepatic encephalopathy (HE), a severe neurological complication of liver dysfunction, has long been regarded as a clinical issue confined to liver disease. However, recent clinical observations and basic research have revealed complex pathophysiological connections between HE and Parkinson's disease (PD), 2 seemingly independent conditions. Patients with HE often exhibit irreversible extrapyramidal symptoms that closely resemble the motor disorders of PD; meanwhile, epidemiological studies suggest that individuals with liver disease-particularly non-alcoholic fatty liver disease (NAFLD)-may face an increased risk of developing PD. From the perspective of the gut-liver-brain axis, this study systematically explores the molecular mechanisms linking HE and PD, proposing a core hypothesis: HE creates a unique "neurotoxic soil" through ammonia toxicity, systemic neuroinflammation, and gut-liver-brain axis dysfunction. This soil may trigger PD in susceptible individuals, accelerate subclinical PD progression, or mimic PD-like pathology. The study analyzes in depth the direct regulatory role of ammonia in α-synuclein (α-syn) aggregation, the impact of liver disease-driven neuroinflammation on microglial activation and α-syn propagation, and the hypothesis of liver-derived α-syn transmission via the gut-liver-brain axis. It further discusses synergistic mechanisms such as manganese deposition, neurotransmitter imbalance, and gut microbiota metabolites. Based on these mechanisms, the study prospects translational medical applications, including the development of diagnostic biomarkers and novel therapeutic strategies such as "ammonia clearance plus" and gut-liver-brain axis targeting. This work provides new insights into how environmental metabolic factors contribute to neurodegenerative diseases and offers a theoretical basis for the combined prevention and treatment of HE and PD.

Mycotoxins are fungi-derived secondary metabolites that pose ecological and human health hazards. Deoxynivalenol (DON), as one of the most prevalent contaminating mycotoxins, has a detrimental impact on intestinal inflammation. Lycopene (LYC), a strong lipophilic carotenoid, is one of the most vital dietary antioxidants for human health. Thioredoxin-interacting protein (TXNIP), as a thioredoxin inhibitory protein, regulates NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation. We performed this work to probe the mechanisms by which LYC antagonizes DON-induced intestinal epithelium damage and the role of TXNIP in it. In the present study, we demonstrated that LYC relieved DON-induced structural and functional injury. We observed that LYC mitigated DON-induced inhibition of cell proliferation and cell cycle arrest, thereby delaying cellular senescence. LYC also mitigated DON-induced activation of TLR4/NF-κB/TNF-α signaling and inflammatory reaction. In addition, LYC prevented DON-induced up-regulation of TXNIP, thus inhibiting NLRP3 inflammasome activation and pyroptosis. Interestingly, TXNIP overexpression reversed the protective effect of LYC on DON-induced pyroptosis and senescence, but NLRP3 inhibitor restored these impairments. Our study suggested that LYC antagonized DON-induced intestinal epithelial cell senescence by suppressing TXNIP-mediated NLRP3 inflammasome activation. These findings show that TXNIP modulates intestinal function and thereby is a new curative molecule for intestinal diseases.

Radiotherapy (RT) and photodynamic therapy (PDT) for breast cancer are limited by tumor hypoxia and suboptimal photosensitizer performance. We developed folate-modified copper-doped carbon dots and loaded them with 5-aminolevulinic acid (ALA) to yield FCA, a nanoplatform that executes cascade nanozyme activities to remodel the tumor microenvironment: decomposing H₂O₂ to relieve hypoxia, generating hydroxyl radicals and singlet oxygen (¹O₂), and depleting glutathione (GSH). This priming enabled efficient ALA-to-protoporphyrin IX conversion, which subsequently amplified reactive oxygen species generation. The elevated oxidative stress then synergized with RT to accumulate DNA double-strand breaks and trigger cell cycle arrest. Consequently, FCA-PDT-RT reduced 4T1 cell viability to 20.09% and induced 83.82% apoptosis outcomes mechanistically linked to nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1)-heme oxygenase 1 (HMOX1) pathway activation. Despite compensatory upregulation of antioxidant genes (HMOX1 and glutamate-cysteine ligase modifier subunit [GCLM]), intracellular GSH and adenosine triphosphate were severely depleted, establishing a metabolic crisis wherein synthesis could not match consumption. This redox/energy collapse drove the pronounced cytotoxicity observed. In an orthotopic 4T1 model, FCA-PDT-RT achieved superior tumor control at only 12 Gy, which correlated with increased CD3⁺/CD8⁺ T cell infiltration and suppressed angiogenesis, while maintaining favorable safety. FCA thus enables synergistic PDT-RT through sequential microenvironment remodeling, oxidative amplification, and metabolic exhaustion, offering a dose-sparing strategy with translational promise for breast cancer therapy.

The worldwide decline in male fertility represents a growing public health challenge, with fluoride exposure recognized as a key environmental factor exacerbating this decline. Fluoride hurts male reproduction, yet the specific mechanism remains unclear. Here, we demonstrate that fluoride reduced mouse sperm quality, destroyed the structure of testicular tissue, and caused severe damage to testicular somatic cells (Leydig and Sertoli cells). Meanwhile, the number of autophagosomes increased in Leydig cells and decreased in Sertoli cells. Network toxicology and functional analysis identified miR-34a-5p as the pivotal miRNA orchestrating fluoride-induced autophagic imbalance in testicular somatic cells. REST was identified as a novel miR-34a-5p target gene exhibiting pro-autophagic activity. Fluoride down-regulates miR-34a-5p and up-regulates REST in Leydig cells, whereas it exerts the opposite effects in Sertoli cells. The rescue experiment elucidated specific mechanisms: Fluoride down-regulates miR-34a-5p in Leydig cells, thereby derepressing REST to activate autophagy. Conversely, in Sertoli cells, fluoride up-regulates miR-34a-5p to suppress REST expression and inhibit autophagy. Collectively, the present study reveals an important mechanism underlying fluoride-induced male reproductive toxicity and provides a potential therapeutic target.

While sleep disorders are a known correlate of social memory deficits, the underlying neurocircuitry and molecular mechanisms remain poorly understood. Using an oxytocin (OXT)-specific sensor imaging approach, we discovered that chronic sleep deprivation (SD) reduced OXT neuropeptide release in the hippocampal CA2 and prelimbic cortex (PrL), thereby disrupting social memory encoding and retrieval processes, respectively. Using fiber photometry recordings and in vitro electrophysiology, we identified the activity of the predominantly OXT-expressing neurons in the paraventricular hypothalamic nucleus (PVN^OXT) were reduced following SD. Specific optogenetic activation of the PVN^OXT-CA2 pathway during encoding phase or PVN^OXT-PrL pathway during retrieval transiently restored SD-induced social memory deficits. Conversely, optogenetic high-frequency activation of PVN^OXT neurons enhanced the function of both PVN^OXT-CA2 and PVN^OXT-PrL pathways, promoting increased OXT release and providing sustained protection against SD-induced social memory deficits. These findings offer causal evidence that the PVN^OXT-CA2 and PVN^OXT-PrL pathways exert distinct modulatory roles in sleep-related social memory deficits and thereby nominate these pathways as precise targets for neuromodulation in sleep-related cognitive disorders.