Research最新文献

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.

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.

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.

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.

The overuse and misuse of antibiotics have led to widespread resistance in bacteria, which makes infections difficult to treat. The insufficient prevention measures, limited treatment options, and delayed antibiotic developments call for immediate global actions to discover effective and safe treatments for bacterial infections. Over the past decades, more and more studies have found that bacterial extracellular vesicles (BEVs) secreted by bacteria with nanoscale size, lipid bilayer structure, pathogen-associated molecular patterns, and inherent bioactive substances are the ideal candidates for bacterial infection treatment. Meanwhile, advanced engineering approaches have further endowed these BEVs with more customizable properties to effectively fight against bacterial infections. Herein, the present review begins with an overview of the biogenesis and biocomponents of BEVs to better comprehend their bioactivities against bacterial infections. Their isolation and engineering approaches are then introduced, with an emphasis on the diverse genetic, physical, and chemical strategies to functionalize them with desirable capacities for the optimal treatment of bacterial infections. Recent advances in exploring the natural BEVs as antibacterial and antiadhesion agents, as well as the engineered BEVs as vaccine antigens, vaccine adjuvants, and delivery nanocarriers, are expounded successively. Discussions on the new trend of engineering BEVs as nanoweapons to combat bacterial infections, in terms of advantages and challenges, are provided at the end to expedite these BEV-based therapeutic modalities for bacterial infections from bench to bedside.

Bioplastics derived from renewable food crops or agricultural feedstocks are alternatives to petrochemical materials, but it is challenging to balance their mechanical properties, thermal stability, and shapeability. Here, we report a thermally stimulated supramolecular bioplastic that employs polyethylene glycol to optimize the assembly of cellulose and polyvinyl alcohol molecules. The resulting bioplastic showed a reinforced supramolecular architecture, with a mechanical elastic modulus of 3.23 GPa and an impact resistance higher than 8.15 kJ·m^-1. It also showed thermal stability from -40 to 135 °C while maintaining its structural integrity and toughness, giving it potential applications for various shaping processes, including weaving, pouring, and molding. The bioplastic could also undergo natural soil biodegradation within 55 d and exhibited promising recyclability and economic feasibility. This study provides a strategy for configuring supramolecular structures and enhancing the design and manufacture of bioplastics with optimal comprehensive properties.

High-precision sensors are of fundamental importance in modern society and technology. Although there are various schemes for the construction of sensors relying on different physical mechanisms, obtaining sensors with higher levels of sensitivity and stronger robustness has always been expected. In particular, non-Hermitian quantum sensors have recently attracted substantial attention due to their unique properties. So far, 2 types of non-Hermitian sensors based on exceptional points and topological zero modes have been realized. Here, high-order exceptional bound states with robust properties are constructed for the first time. Based on these states, we propose theoretically and demonstrate experimentally another new type of non-Hermitian quantum sensors. Such sensors not only are robust against disorders but also have unprecedented sensitivity. Their sensing performance can display the improvement of many orders of magnitude over the previous non-Hermitian sensors. Furthermore, we design and fabricate such sensors based on circuit networks. Taking weak magnetic field detection as an example, we also experimentally demonstrate their sensing capabilities. Our work opens up new avenues for the development of highly sensitive sensors, which have a wide range of applications in various fields.