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Aberrant deposition of ¦Â©\amyloid (A¦Â) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer's disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that alleviates AD pathology by modulating ¦Â©\site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen©\activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, A¦Â plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed A¦Â oligomer©\induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c©\Jun N©\terminal kinase (JNK) and extracellular signal©\regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease©\modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease©\modifying candidate with the potential to drive a breakthrough approach targeting AD pathology. Ramalin alleviates Alzheimer's disease pathology by selectively inhibiting HDAC6, reducing BACE1 levels, and suppressing neuroinflammation through downregulation of the NLRP3 inflammasome and iNOS. It restores synaptic function impaired by A¦Â toxicity and improves cognitive performance in AD mouse models, APP/PS1 and 3xTg©\AD. Additionally, ramalin modulates the MAPK signaling pathway, reducing tau phosphorylation by inhibiting JNK and ERK activation.

IntroductionTumor-associated macrophages (TAMs) promote immunosuppression, hindering immune checkpoint blockade and immunotherapy efficacy. To overcome this, we developed a novel multifunctional nanovaccine based on hepatitis B core virus-like particles (HBc VLP) to synergistically remodel the immunosuppressive tumor microenvironment through integrated TAM reprogramming and B7-H3 checkpoint blockade.MethodsThe core VLP co-displayed tumor antigen peptide MAGE-A10 and TAM-targeting peptide M2pep via fusion expression. Immunostimulatory CpG oligodeoxynucleotide 1826 (CpG) was encapsulated within VLP. Anti-B7-H3 antibody (¦ÁB7-H3) and polyethylene glycol (PEG) were chemically conjugated to the surface for checkpoint blockade and prolonged circulation, forming CpG@VLP-¦ÁB7-H3-PEG.ResultsStructural characterization using transmission electron microscopy and dynamic light scattering confirmed the hollow spherical self-assembly of VLP. Nanovaccines efficiently targeted TAMs in vitro and in vivo. Following CpG encapsulation (5.60 ?g/mg), the nanovaccine reprogrammed M2-like TAMs into an M1-like phenotype. This was achieved by elevating the M1/M2 ratios of CD86/CD206 and MHC II/CD206 to 15.50-fold and 3.11-fold, respectively, as determined by flow cytometry. Further conjugation of ¦ÁB7-H3 (250 ?g/mg) significantly enhanced T-cell activation in TAM-T cell co-culture assays. In B16-F10 melanoma-bearing mice, reprogrammed iNOS+ M1-like macrophages triggered robust antitumor immunity, achieving a tumor inhibition rate of 63.47%. These macrophages also function as antigen-presenting cells and increase the proportion of tumor-infiltrating Granzyme B+CD8+ T cells. ¦ÁB7-H3 conjugation further boosted infiltrating immune cells, M1-like macrophages, activated CD69+CD4+/CD8+ T cells, and cytotoxic T lymphocytes. PEGylation amplified systemic tumor-specific immunity and increased tumor inhibition by 80.12%.ConclusionThis HBc VLP-based nanovaccine constitutes a pioneering multifunctional platform designed to overcome TAM-mediated immunosuppression through synergistic integration of three modalities: antigen presentation, TAM phenotype reprogramming, and B7-H3 checkpoint blockade. To the best of our knowledge, this is the first nanovaccine architecture to enable coordinated immunomodulation. Its modular design supports the clinical translation of solid tumors and personalized immunotherapy. Graphical Abstract

Atopic dermatitis (AD) is a chronic dermatological disorder characterized by intense pruritus and eczematous lesions. Repeated topical application of 2,4-dinitrofluorobenzene (DNFB) in NC/Nga mice produces AD-like clinical symptoms that closely resemble human AD. N-acetyl-L-alanine (L-NAA), a derivative of L-Alanine, has unknown biological and physiological effects on cutaneous tissue. In this study, we investigated whether L-NAA modifies AD-like symptoms elicited by ongoing DNFB exposure in NC/Nga mice. Topical administration of L-NAA markedly attenuated the development of AD-like cutaneous lesions triggered by DNFB. L-NAA treatment further suppressed DNFB-induced infiltration of eosinophils and mast cells and prevented the increase of serum IgE resulting from DNFB application. L-NAA treatment decreased DNFB-stimulated expression of IL-4, a Th2-associated cytokine, but increased IFN-¦Ã expression, indicative of Th1 activity, within the skin lesions. In addition, L-NAA prevented the DNFB-driven upregulation of GATA3, a central regulator of Th2 lineage differentiation, in CD4£« cells, with no effect on T-bet, the principal regulator of Th1 cells. These findings indicate that L-NAA can limit Th2 differentiation in the AD mouse model. Therefore, L-NAA may serve as a promising therapeutic and immunomodulatory compound against AD.