Research最新文献

Adipose tissue has evolved from a passive lipid store to a dynamic, heterogeneous endocrine organ, whose dysfunction is closely linked to a cluster of chronic metabolic diseases. While early studies focused on overall adiposity, emerging evidence demonstrates that depot-specific adipose tissue traits outperform body mass index alone in predicting various disease risks. Adipose tissue heterogeneity refers to the inherent differences across distinct adipose depots, which manifest at anatomical, cellular, and molecular levels, alongside functional specialization. Moving beyond descriptive characterization, this review proposes a multiscale, functionally grounded framework that translates adipose heterogeneity into precision risk management and depot-targeted therapies. We provide a holistic update to cover previously underappreciated adipose depots (perivascular, epicardial, and bone marrow adipose tissues) and integrate recent single-cell sequencing discoveries of novel cell subsets in adipose tissues. We systematically summarize the core hallmarks of adipose heterogeneity and depot-specific roles in health and disease, while assessing the strength of evidence linking cellular subsets to functional outcomes. We also discuss how emerging technologies such as spatial transcriptomics, organoid technology, and artificial intelligence-driven imaging analysis resolve pathogenic niches and build translatable risk models. Finally, we propose a translational framework to overcome key bottlenecks from preclinical validation to clinical implementation, aiming to advance personalized management of diseases related to adipose tissue dysfunction.

Deoxynivalenol (DON), a mycotoxin produced by Fusarium species, is a major and unavoidable environmental contaminant that poses serious risks to intestinal health. Lycopene (LYC), a natural carotenoid with potent antioxidant properties, has been reported to exert protective effects against oxidative stress. Phosphoglycerate mutase family member 5 (PGAM5) acts as a key signaling hub to control mitochondrial dynamics and mitophagy. This study aimed to elucidate the potential role of LYC in DON-induced intestinal damage and clarify the contribution of PGAM5. We established intestinal porcine epithelial cell models to explore the effects of DON and LYC on intestinal barrier integrity, mitochondrial function, mitophagy, and ferroptosis through assessments of cell viability, oxidative stress, iron accumulation, and autophagic activity. Mechanistic insights were validated using RNA sequencing, molecular docking, Western blotting, and immunofluorescence analyses. PGAM5 expression was modulated via plasmids and small interfering RNA. Our results demonstrated that DON disrupted barrier integrity, reduced cell motility, and induced cytoskeletal disorganization, accompanied by excessive mitophagy, lipid peroxidation, and ferrous iron accumulation, ultimately leading to ferroptosis. Notably, LYC alleviated DON-induced intestinal damage by inhibiting mitophagy and ferroptosis. Importantly, PGAM5 overexpression abolished the protective effects of LYC, indicating that PGAM5-mediated mitophagy-dependent ferroptosis plays a critical role in DON-induced intestinal damage. These findings suggest that LYC may serve as a potential therapeutic strategy for treating mycotoxin-induced intestinal disorders.

Extracellular vesicles (EVs) are promising cell-free therapeutics for diabetic wound healing due to their immunomodulatory and proangiogenic properties. Nonetheless, challenges in ensuring long-term stability and achieving targeted delivery continue to impede clinical translation. Herein, we developed a 3-dimensional bioprinted methacrylated decellularized umbilical cord matrix (MDUM) patch enabling the sustained delivery of telomerase-immortalized umbilical cord mesenchymal stem cell-derived EVs (TMSC-EVs). TMSC-EVs encapsulated in MDUM maintained their structural integrity and biological functionality for more than 30 d under 4 °C storage, outperforming those encapsulated in gelatin methacryloyl (P < 0.01). In a diabetic murine wound model, our data demonstrated that MDUM could enhance the retention and delivery of TMSC-EVs and further augment the therapeutic effects for diabetic wound healing as revealed by attenuating proinflammatory cytokine levels, enhancing neovascularization, and accelerating collagen deposition. This study pioneers the integration of biomaterial engineering with immortalized cell-derived EVs, establishing a translatable platform for regenerative therapies in chronic wound management.

The mammillary body (MB) has traditionally been regarded as a relay station for the hippocampus and plays a pivotal role in the Papez circuit. However, its molecular and cellular organization remains inadequately characterized. This study focuses on the horizontally symmetrically distributed neurotensin (Nts)-expressing and nitric oxide synthase 1 (Nos1)-expressing neurons in the MB, demonstrating that Grik4 (encoding a high-affinity kainate receptor subunit) underlies their distinct electrophysiological properties. Within neural circuits, Nts and Nos1 neurons receive excitatory inputs from the ventral subiculum and send parallel excitatory projections to the dorsomedial and ventrolateral subdivisions of the anteroventral thalamus (AV). These 2 cell type-specific circuits are essential for working memory and exhibit selective activation during the maintenance phase with a marked temporal difference. Together, our findings establish a direct link from molecular identity to circuit architecture and cognitive processing by demonstrating that molecularly distinct Nts and Nos1 neurons constitute differential circuits with convergent inputs, divergent outputs, and dissociable roles in working memory maintenance. This work thus reveals a fundamental cross-scale organizational principle-molecule, cell, circuit, function-within the MB.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host immune response to infection, initiated by an excessive inflammatory cascade that frequently progresses to immunoparalysis characterized by immune cell dysfunction. In this review, we first provide an overview of the key elements and stages in the onset and progression of sepsis. Subsequently, we discuss the recent advances of biomaterial-based nanomedicine (including organic nanomaterials, inorganic nanomaterials, and natural bio-inspired nanomaterials) in the treatment of sepsis. The elimination of pathogens and the modulation of the immune response within the sepsis microenvironment through the design of diverse biomaterial systems were specifically summarized. Finally, we discuss the challenges and opportunities for biomaterial-based nanomedicine in the treatment of sepsis.

Recent advances in transcranial ultrasound stimulation (TUS) pulsed at 40 Hz have demonstrated the potential to ameliorate cognitive deficits in mouse models of Alzheimer's disease. However, technical barriers remain as general anesthesia is required for mice, which restricts the accurate elucidation of biological mechanisms and behavioral effects under awake physiological conditions. Here, we report a wearable, free-moving ultrasound stimulation system that delivers TUS pulsed at 40 Hz to female 5xFAD transgenic mice to systematically evaluate the behavioral outcomes and underlying mechanistic pathways. Among the treatment groups, a 14-d regimen at an acoustic intensity of 2.14 W/cm² yielded the optimal cognitive outcome in Alzheimer's disease mice, which was consistently verified across Y-maze and Morris water maze tests. Additionally, this group showed reduced Aβ plaque deposition and increased plaque-associated microglial activity. Furthermore, enhanced gamma oscillations in the hippocampus were detected following treatment. RNA sequencing revealed modulation of innate immune and inflammatory pathways. Corresponding molecular analysis demonstrated a marked down-regulation in RIPK1, phosphorylated NF-κB, and necroptosis markers, alongside reductions in key pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α). Collectively, our findings suggest that the cognitive improvement observed after treatment with TUS pulsed at 40 Hz may be linked to the modulation of neuroinflammatory and necroptotic pathways, possibly involving RIPK1/NF-κB signaling.

[This corrects the article DOI: 10.34133/research.0625.].

The rise of multidrug-resistant bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), poses a serious threat to human health, necessitating an urgent need to develop innovative antibacterials with multifunctions for this. Here, focusing on integrating multi-antimicrobial mechanisms with visual monitoring, we report a novel phenanthro[9,10-d]imidazole fluorogen 9b, outstanding for its antibacterial effects against S. aureus and various clinical MRSA isolates (minimum inhibitory concentration = 0.5 to 1 μg/ml) with rapid bactericidal activity, high membrane selectivity, and low susceptibility to drug resistance. Further investigation revealed its dual antimicrobial mechanisms of action by concurrently disrupting bacterial cell membranes and inducing bacterial DNA degradation to accelerate bacterial death. Ultraviolet-visible and fluorescence spectroscopy studies showed that the fluorescence intensity of 9b was dramatically enhanced when it interacted with S. aureus. Notably, in vivo studies demonstrated that 9b effectively treated both skin and thigh MRSA infections, showing a favorable safety profile and superior efficacy compared to the first-line antibiotic vancomycin. The "dual-mechanism" fluorescent phenanthro[9,10-d]imidazole fluorogen 9b holds promise as a candidate for developing innovative antibacterial agents that enable simultaneous real-time diagnosis and treatment.

Expanding near-field regions in high-frequency 6G systems necessitates precise spatial-field control, yet narrow beamwidths and 3-dimensional tracking complexities create severe alignment hurdles. Here, we present an eye-tracking-driven programmable metasurface that bridges human visual intent with real-time electromagnetic responses via gaze-contingent beam steering. The system integrates a polarization-agile metasurface featuring independent 1-bit phase control for both copolarized and cross-polarized reflections. By engineering a 90° phase offset between these channels, the eye-tracking-driven programmable metasurface enables high-gain beam focusing and efficient linear-to-circular polarization conversion. Experimental results confirm that the system dynamically maps 3-dimensional gaze coordinates to metasurface coding patterns with millisecond-level responsiveness, facilitating robust near-field focusing and far-field scanning. This work establishes a "service-follows-vision" communication scenarios for intelligent wireless systems, offering distinct advantages in signal enhancement and interference mitigation.

Mitochondrial DNA (mtDNA) damage and its subsequent release into the cytoplasm are strongly linked to osteoarthritis (OA), but the pathogenic mechanism remains poorly understood. Here, this study reveals that under inflammatory or oxidative stress, the down-regulation of mitochondrial base excision repair enzyme 8-oxoguanine DNA glycosylase 1 and excessive opening of the mitochondrial permeability transition pore jointly drive mtDNA escape into the cytoplasm. Activation of 8-oxoguanine DNA glycosylase 1 with TH10785 reduces the production of oxidized mtDNA and preserves mtDNA integrity, while suppression of excessive mitochondrial permeability transition pore opening with cyclosporin A prevents mtDNA translocation. The combined intervention synergistically decreases cytosolic mtDNA levels, alleviating cartilage matrix degradation and cellular senescence. Mechanistically, cytosolic mtDNA induces the senescence-associated secretory phenotype by activating the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes-nuclear factor κB signaling axis, whereas combined intervention blocks this cascade activation. Notably, intra-articular injection of the combination of TH10785 and cyclosporin A markedly reduces senescence and ameliorates the progression of the experimental OA model mice. This research reveals the dual regulatory roles of mtDNA integrity and translocation in governing cytosolic mtDNA content, providing novel insights for developing mtDNA-targeted therapeutic strategies against OA.