Intracerebral hemorrhage (ICH), a severe cerebrovascular disorder with high mortality, leads to secondary brain injury (SBI) primarily through neuroinflammation and blood-brain barrier (BBB) disruption. Among the pathological cascades, excessive activation of macrophages and the CCR5/JAK1/STAT1/MMPs signaling pathway play pivotal roles in amplifying neuronal damage. Apigenin (API), a natural flavonoid with anti-inflammatory and neuroprotective properties, has emerged as a promising therapeutic candidate to counteract these processes. In this study, we developed apigenin-loaded PLGA nanoparticles functionalized with DSPE-PEG2000-RVG29 and DSPE-PEG2000-folic acid (RVG/FA-NPs@API) to achieve targeted delivery to inflammatory macrophages and investigated their therapeutic effects against SBI after ICH. In a murine ICH model, API administration significantly improved neurological outcomes, reduced cerebral edema, suppressed neuronal apoptosis, and preserved BBB integrity. Mechanistically, API bound covalently to JAK1 at Cys1052, inhibiting its phosphorylation and subsequently downregulating the CCR5/JAK1/STAT1/MMPs cascade. Furthermore, RVG/FA-NPs@API demonstrated excellent stability, efficient brain-targeting, and superior biocompatibility, achieving enhanced therapeutic efficacy compared with free API. These findings highlight a novel strategy for targeted immunomodulation and provide translational insights into nanoparticle-assisted delivery of natural compounds for the treatment of ICH-induced SBI.

Background. The repair and regeneration of large bone defects represent highly challenging tasks in bone tissue engineering. Although recent studies have shown that osteogenesis is stimulated by periodic heat stress, the thermal regulation of osteogenic differentiation in ectomesenchymal stem cells (EMSCs) is not well studied. Methods and Results. In this study, the direct effects of periodic heat stress on the differentiation of EMSCs into osteoblasts were investigated. EMSCs derived from rat nasal respiratory mucosa were seeded onto culture plates, followed by 1h of heat stress at 41C every 7 days during osteogenic differentiation. Based on the results of the present study, periodic heating increases alkaline phosphatase (ALP) activity, upregulates osteogenic-related proteins, and promotes EMSC mineralization. In particular, increased YAP nuclear translocation and YAP knockdown inhibited osteogenic differentiation induced by heat stress. Furthermore, the expression and activity of transglutaminase 2 (TG2) were significantly increased after YAP nuclear translocation. Conclusion. Together, these results indicate that YAP plays a key role in regulating cellular proteostasis under stressful cellular conditions by modulating the TG2 response.

Background: Intracerebral hemorrhage (ICH) is a severe stroke subtype associated with high mortality and long‐term disability, for which no effective treatment currently exists. Vinorine (Vin), a monoterpene indole alkaloid derived from Rauvolfia reflexa , has been traditionally used for age‐related neurological disorders, yet its therapeutic potential and mechanisms in ICH remain unclear. Methods: An ICH mouse model was established via intracranial collagenase injection. Vin was administered intraperitoneally at varying doses, and its effects on motor function, sensory deficits, and neural regeneration were evaluated. Network pharmacology was employed to predict potential targets and pathways, followed by validation through molecular docking, in vivo experiments, and in vitro assays. Results: Network pharmacology identified four core targets and 35 related pathways, with JAK2 as a central node. In vivo, Vin significantly improved motor deficits, reduced cerebral edema, preserved blood–brain barrier integrity, and promoted hematoma resolution. These effects were mediated through modulation of the CXCR2–JAK–STAT axis and suppression of JAK2 phosphorylation. In vitro, Vin inhibited JAK–STAT activation in microglia, downregulated MMP expression, and facilitated the transition from M1 to M2 phenotypic polarization. Additionally, Vin enhanced the expression of neuronal markers (NF200, PSD95, GAP43) and reduced neuronal apoptosis. Conclusion: Vin attenuates neurological deficits after ICH likely by inhibiting MMP expression in microglia via regulation of the CXCR2–JAK–STAT pathway. These findings highlight the therapeutic potential of Vin and provide mechanistic support for its further development as a treatment for ICH.