Research最新文献

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.

Upon tumor metastasis, lymph nodes (LNs) undergo mechanical stiffening, yet how this change influences T cell activation within the microenvironment remains incompletely understood. In particular, the dynamic mechanical forces during activation are transduced by cell-extracellular matrix (ECM) interactions, while cell-cell interactions persist. Here, we established a novel T cell culture platform using hydrogels with tunable stiffness and decoupled presentation of RGD peptide and anti-CD3 monoclonal antibody, separately mimicking ECM-T cell and T cell-antigen-presenting cell interactions. This platform closely mimics the LN microenvironment during T cell activation. By integrating experiments with mathematical modeling, we revealed that T cells sensed mechanical changes in the microenvironment requiring RGD/integrin ligation, while stiff matrix up-regulated F-actin aggregation instead of myosin contraction, deforming the nucleus and promoting yes-associated protein nucleus translocation, resulting in interleukin-2 expression and T cell activation. Our findings shed light on the mechanobiological mechanism underlying the potential benefits of immunotherapy in patients with LN metastases and provide an optimized mechanical platform for studying T cell activation and expansion in vitro.

Lightweight multifunctional aerogels hold great promise in applications, e.g., electromagnetic microwave absorption, thermal insulation, and acoustic damping. However, conventional aerogels often suffer from limited functionalities, complicated manufacturing, and poor sustainability. Metal-organic frameworks (MOFs), with tunable porosity and abundant active sites, offer a compelling route to high-performance multifunctional aerogels, but it has remained a grand challenge to develop sustainable multifunctional MOF-based aerogels. Here, we report a sustainable multifunctional bio-aerogel (Ni-CCA) by integrating hierarchical scale-like topological Ni-MOF-NH₂ with cellulose through simple pretreatment using deep eutectic solvent followed by stepwise assembly-carbonization. The resulting aerogel features an ultralow density and a 3-dimensional layered porous structure. With 5 wt.% filler loading, Ni-CCA achieves a minimum reflection loss (RL_min) of -53.47 dB and an effective absorption bandwidth of 4.42 GHz, along with a radar cross-section suppression of 27.90 dB·m². Additionally, Ni-CCA shows enhanced flame retardancy (64.3% reduction in peak heat release), low thermal conductivity [33.3 mW/(m·K)] and improved acoustic damping (NRC of 0.31, 15 to 23 dB attenuation). The multifunctionalities of this bio-aerogel stem from its hierarchical architecture and synergistic loss mechanisms, offering a promising strategy for creating the next generation of lightweight multifunctional protective materials.

Stretchable conductive hydrogel composites with infrared stealth and electromagnetic interference (EMI) shielding are in high demand for aerospace, military, and soft robotics. However, realizing stable and efficient performance with low conductive filler content under harsh conditions remains a substantial challenge. Herein, a flexible multifunctional double network hydrogels with high performance and environmental stability was constructed via transition metal carbide/nitride (MXene)/(NH₄)₂SO₄-treated strategy-assisted ultrasonic dispersion and thermal polymerization method. The synergistic effect of MXene and (NH₄)₂SO₄ within the hydrogel system led to a 3-fold enhancement in mechanical properties, 20-dB improvement in EMI shielding effectiveness, and 40% enhancement in the gauge factor with only 0.12 wt % conductive filler. Benefiting from its high conductivity, efficient thermal insulation, and composite network structure, the double network hydrogels maintain stable EMI shielding and infrared stealth performance under various harsh conditions including repeated stretching, prolonged water evaporation, low-temperature freezing, high-temperature heating, alcohol lamp flame exposure, and high-strain stretching. These findings demonstrate that the hydrogels combine ultra-low filler efficiency, environmental robustness, and multifunctional adaptability, making it a promising candidate for next-generation aerospace, military, and wearable electronic applications.