Structural tissue alterations in numerous brain disorders can initiate mechanosensory signaling pathways and influence neuropathology. Astrocytes are highly mechanosensitive cells that play essential roles in maintaining brain homeostasis; however, the molecular mechanisms underlying astrocyte mechanosensation during pathological conditions remain largely unexplored. In this study, we investigated how the expression of the mechanosensitive ion channel Piezo1 in astrocytes is modulated by inflammatory triggers. We found that direct exposure of primary astrocyte cultures to inflammatory stimuli, including lipopolysaccharide (LPS) or oligomeric amyloid-β (oAβ), had minimal impact on astrocytic Piezo1 expression. In contrast, when LPS or oAβ were applied to primary microglia cultures, Piezo1 expression was increased in microglia, and conditioned media from these microglia cultures significantly upregulated Piezo1 expression in astrocytes. We further identified that microglia released pro-inflammatory cytokines (IL-1α, IL-1β, and TNF-α) that can directly enhance Piezo1 expression and Piezo1-mediated Ca2+ signaling in both rodent and human astrocytes. Microglial depletion in 5xFAD mice consistently and substantially reduced astrocytic Piezo1 expression in vivo, supporting the physiological relevance of this microglia-astrocyte signaling axis during pathology. Activation of Piezo1 with Yoda2 did not alter astrocytic inflammatory gene expression under basal conditions but reduced TNF-α, CCL2, and C3 expression following cytokine pretreatment. Conversely, Piezo1 knockdown increased GFAP expression at baseline and enhanced pro-inflammatory gene expression under cytokine stimulation, indirectly promoting microglial activation. These findings demonstrate that astrocytic Piezo1 expression is regulated by microglia-derived inflammatory signals and plays a context-dependent role in modulating astrocyte reactivity and neuroinflammatory responses.

Inflammaging, defined as the persistent, low-grade sterile inflammation accompanying aging, represents a central driver of age-related pathology, including cardiovascular dysfunction, neurodegeneration, metabolic disorders, and frailty. This review discusses the most recent advances in understanding its mechanistic basis, encompassing cellular senescence, the senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, immune cell senescence, innate immune hyperactivation, defective inflammatory resolution, and nutrient-sensing dysregulation. Single-cell and spatial transcriptomics reveal tissue-specific and context-dependent patterns, highlighting the systemic complexity of inflammaging. Preclinical interventions demonstrate that inflammaging is modifiable through senolytics, which selectively eliminate senescent cells, and senomorphics, which suppress SASP without inducing cell death. Metabolic modulators such as metformin and rapamycin attenuate inflammatory signaling, while immune-directed therapies and microbiome-targeted interventions provide synergistic benefits through combinatorial approaches. Early-phase clinical trials in frail older adults show feasibility, safety, and preliminary efficacy, including reductions in circulating inflammatory markers, improved physical function, and enhanced immune responsiveness. Inflammaging trajectories are shaped by lifestyle, environmental exposures, and evolutionary factors, underscoring the need for personalized interventions. Remaining challenges include biomarker development, long-term safety evaluation, and heterogeneity across aging populations. Addressing these through interdisciplinary research supports a precision geroscience paradigm, where multimodal targeting of inflammaging can extend healthspan and reduce chronic disease burden.

The key for nanozymes to achieving sequential infection-inflammation-repair in wound infection therapy and healing lies in how to resolve the contradiction of reactive oxygen species (ROS) regulation between antibacterial therapy and anti-inflammation. Herein, a freestanding pristine CuGeO3 (CGO) nanozyme film (NF) composed of nanowires is first designed and simply synthesized. Such a NF with flexibility, wet tissue adhesion properties, alongside water/blood absorbing capability could serve as a wound dressing and present superb antibacterial/antibiofilm efficacy for photothermal/chemodynamic synergistic therapy of wound infection owing to its extraordinarily outstanding photothermal performance, and glutathione depletion-enhanced peroxidase-like activity to generate ROS in acidic infection microenvironments (IMEs). Attractively, it is disclosed that after completing infection therapy, the enzyme activity of this CGO NF automatically and continuously switches into catalase-like activity to eliminate ROS as IMEs switches into neutral microenvironments. This promotes the M2 phenotype polarization of macrophages to relieve inflammation and accelerate wound repair. Furthermore, the longer and entangled nanowire structure of the CGO NF prone to retention in the wound site minimizes its toxicity to healthy tissues. Overall, it is the first paradigm to leverage a photothermal NF consisting of inorganic nanomaterials only as a wound dressing. Based on such a safe, effective, activity-switchable NF dressing, adaptive infection-inflammation-repair cascade in wound infection therapy and healing has been realized, achieving 98.7% wound closure within 10 days. We believe this work will foster the therapeutic application of activity-switchable nanozymes, and provide meaningful insights into nanozymes-based wound infection therapy and healing.

Atopic dermatitis (AD) is a chronic inflammatory skin lesions. Mitochondrial dysregulation is associated with various pathologic conditions, including inflammation in the skin. Prior research has indicated that Erianin, a naturally occurring compound derived from Dendrobium plants, has antioxidant and anti-inflammatory effects. Generally, Erianin has been demonstrated to be effective in cutaneous melanoma and ulcerative colitis. However, there is limited knowledge regarding its biological components and the mechanisms by which it prevents and treats AD. To investigate the protective effects of Erianin against AD and to elucidate the potential mechanism of inflammation in AD, with a particular focus on the role of mitochondrial impairment pathways. Combined with vivo and vitro models of inflammation was employed to assess skin conditions, oxidative stress, and mitochondrial dysfunction. The mitochondrial homeostasis was analyzed, and the effects of Erianin treatment on these processes were evaluated using histological analysis, biochemical assays, molecular techniques, and targeting inflammatory cytokines, oxidative stress, mitophagy, and apoptosis. Erianin effectively alleviated AD, and computational simulations suggested a potential interaction with PINK1. Treatment with Erianin significantly reversed these dysfunctional states by promoting mitophagy activity, thereby alleviating mitochondrial dysfunction and reducing ROS levels, which ultimately suppressed apoptosis. These findings demonstrate that Erianin exerts therapeutic potential in AD by targeting mitophagy, with PINK1/Parkin-mediated mitophagy playing a crucial role in the pathogenesis of AD.

Multifocal skeletal tuberculosis is an uncommon manifestation of osteoarticular tuberculosis characterized by noncontiguous involvement of multiple skeletal sites. When associated with a mass-like pulmonary lesion, it may closely simulate disseminated malignancy. We report a 26-year-old immunocompetent male presenting with progressive neck stiffness, fever, cough, weight loss, and dysphagia. Imaging demonstrated a large right upper lobe mass with internal air bronchograms and associated centrilobular tree-in-bud nodules, along with multifocal destructive lesions involving the cervical, thoracic, and lumbar spine, sternum, sacroiliac joint, and pelvic bones. Extensive posterior-element involvement was present, with associated prevertebral, paraspinal, and epidural soft-tissue collections resulting in early spinal cord compression. Laboratory evaluation revealed elevated inflammatory markers, a strongly positive Mantoux test, and negative HIV serology. Bronchoalveolar lavage was negative for malignancy and acid-fast bacilli. Histopathological examination of a CT-guided biopsy demonstrated granulomatous inflammation with Langhans-type giant cells, while GeneXpert MTB detected Mycobacterium tuberculosis, confirming the diagnosis. The constellation of a pulmonary mass and multifocal destructive skeletal lesions initially raised strong suspicion for disseminated metastatic disease. This case highlights an uncommon radiologic phenotype of tuberculosis that closely mimics malignancy and underscores the importance of maintaining a high index of suspicion and obtaining early tissue diagnosis to facilitate appropriate management.

To achieve accurate and high-efficient quantitative detection of three serum biochemical indicators (SBIs), namely glucose (GLU), triglycerides (TG), and total cholesterol (TC), this study proposes a bimodal spectroscopy method integrating multi-wavelength time-resolved photoacoustic spectroscopy (TR-PAS) with near-infrared spectroscopy (NIRS), combined with a deep learning (DL) approach. A total of 35 characteristic wavelengths (12 for GLU, 13 for TG, and 10 for TC) are determined from the energy-corrected photoacoustic (PA) peak-to-peak value spectra of biochemical standard solutions by integrating three wavelength selection methods. NIR spectra and time-resolved PA signals at the selected wavelengths are experimentally collected from 1084 serum samples. Following data augmentation for the bimodal data and data preprocessing for NIR spectra, a dual-branch DL network, namely DB-CNN-LSTM-MAM model, was established to quantitatively predict GLU, TG, and TC, respectively. Through optimization of the model structure and parameters, the root mean square error of prediction (RMSEP) and coefficient of determination (Rp²) for the testing set were as follows: GLU: 0.9653 mmol/L, 0.9296; TG: 0.3956 mmol/L, 0.9575; TC: 0.4443 mmol/L, 0.9290. The generalization of the established DL model is verified by using 10-fold cross validation, and the external independent samples. The quantitiative performances of three SBIs are compared with other DL models. To validate the effectiveness of the proposed method, the comparisons are also performed between the bimodal spectroscopy and unimodal spectroscopy, as well as between the multi-wavelength TR-PAS-NIRS and the single-wavelength TR-PAS-NIRS. The study results indicate that the proposed method provides an accurate and highly efficient candidate solution for the quantitative detection of SBIs of ex vivo serum.

Evidence indicates that nuclear receptor subfamily 1 group H member 3 (NR1H3) activation mitigates sepsis-induced acute lung injury (SALI) by reducing inflammatory response. Nevertheless, the mechanisms underlying NR1H3-inflammation interactions in addressing SALI remain unclear. Moreover, limited phytochemicals have been documented to ameliorate SALI via this pathway. Here, we discovered that NR1H3 activation directly suppresses the clustering of toll-like receptor 4 (TLR4) to lipid rafts, which acts as a part of the priming of NLR family pyrin domain containing 3 (NLRP3) inflammasome. This process results in the suppression of NLRP3 inflammasome assembly and activation, consequently alleviating gasdermin-D (GSDMD)-mediated pyroptosis. Furthermore, through dual-luciferase reporter gene testing, drug binding assays, gene expression analysis, and biochemical evaluation, we determined lappaconitine hydrobromide (LAH) as a novel NR1H3 agonist that effectively suppresses TLR4-NLRP3 signaling pathway. Our results showed LAH attenuates inflammatory lung injury in both lipopolysaccharide (LPS) and cecal slurry (CS)-induced SALI mouse models. In vivo and in vitro experiments revealed that LAH suppresses NLRP3 signaling activation and pyroptosis. Additionally, RNA sequencing (RNA-seq) and bioinformatics analysis demonstrated that the differentially expressed genes (DEGs) linked to interleukin-1 beta (IL-1β) production, modulation of inflammatory response, and control of innate immune response were markedly enriched in LAH, and core genes amongst the DEGs included NR1H3. Mechanistically, LAH reduces inflammation and pyroptosis through modulation of NR1H3-NLRP3-GSDMD axis in mice. This finding was further substantiated by the suppression of NR1H3 in vitro. Our findings offer novel perspectives on the NR1H3-inflammation interaction in SALI regulation and indicate the therapeutic promise of LAH as an NR1H3 agonist for SALI management via NLRP3 suppression.

Macrophages are sentinel innate immune cells that arise from embryonic precursors and bone marrow monocytes, displaying a functional continuum that transcends the classical M1 (pro-inflammatory)/M2 (anti-inflammatory) dichotomy. Under homeostatic conditions, balanced M1/M2 polarization preserves tissue integrity by coordinating immune surveillance, efferocytosis, and tissue repair. When this equilibrium is disrupted, however, M1-skewed responses drive chronic inflammation and autoimmunity, whereas M2-skewed polarization facilitates tumor immune evasion and organ fibrosis. Although diverse therapeutic strategies-including reprogramming, depletion, blockade of monocyte recruitment, CAR-M cells, and nanomedicine-are being explored to restore homeostasis, clinical translation remains constrained by the lack of pathogenic subset-specific markers, insufficient predictive biomarkers for patient stratification, species divergence between mice and humans, and the temporal complexity of context-dependent intervention windows. In this Review, we systematically delineate macrophage plasticity and the molecular mechanisms underlying polarization imbalance, evaluate existing and emerging macrophage-directed interventions, and dissect these translational bottlenecks in depth, highlighting how single-cell multi-omics, humanized models, and dynamic biomarkers can overcome them. By providing a roadmap for precisely calibrating macrophage functional states and restoring M1/M2 balance, this framework will accelerate the development of precision immunotherapies aimed at re-establishing immune homeostasis across a broad spectrum of human pathologies.

Chronic inflammatory conditions including arthritis, psoriasis, inflammatory bowel disease, and pulmonary fibrosis are increasing due to adverse effects of current steroidal and non-steroidal anti-inflammatory drugs (NSAIDs). This study hypothesizes that bioactive peptides derived from underutilized marine species could serve as a safer and effective alternative to NSAIDs. This study aims to explore the anti-inflammatory potential of oligopeptides derived from the muscle (SM) and visceral mass (SV) of the Pygmy ribbontail catshark (Eridacnis radcliffei) using enzymatic hydrolysis. The results revealed that the amino acid composition of SM and SV, determined by chromatographic analysis, showed presence of both essential and non-essential amino acids, including glutamic acid, alanine, and tyrosine. Enzymatic hydrolysis with alcalase and trypsin at the 12th hr yielded the highest anti-inflammatory activity, with protein denaturation inhibition (82.69 ± 2.74%; 75.84 ± 2.65%) and membrane protection (45.67 ± 2.98%; 59.98 ± 3.52%) for SM and SV, respectively. The active peptides, identified as ETPVP (from SM) and VDGQL (from SV) through LC-MS/MS, demonstrated good solubility and foaming stability across a pH range of 2-10. In vitro studies on LPS-stimulated RAW264.7 macrophage cells confirmed that both peptides, at 200 µM, were non-cytotoxic and significantly suppressed nitric oxide production. These findings highlight the novelty of isolating anti-inflammatory peptides from underutilized marine species and their potential applications in developing alternative therapies for chronic inflammatory conditions.