Queen Saovabha Memorial Institute

Excessive inflammation in sepsis and systemic lupus erythematosus (SLE) is driven by immune dysregulation involving conventional dendritic cells (cDCs), which regulate adaptive immunity, and macrophages, which mediate inflammation and tissue repair. The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating these innate immune cells, suggesting that targeting AhR is a promising strategy to mitigate hyperinflammation in sepsis and SLE. In this study, we demonstrate that phthiocol, a vitamin K analog and AhR ligand, ameliorates hyperinflammation and improves outcomes in both cecal ligation and puncture (CLP)-induced sepsis and Fcgr2b^-/- lupus mouse models. Phthiocol-treated bone-marrow-derived dendritic cells (BM-cDCs) displayed a tolerogenic-like phenotype with increased IL-10 and CD206 expression, and promoted regulatory T cell (Treg) proliferation and IL-10 production, while suppressing IL-17-producing T cell responses. Phthiocol induced M2-like polarization in bone-marrow-derived macrophages (BMMs) with high IL-10 production, in contrast to other AhR ligands, including 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 6-Formylindolo[3,2-b]carbazole (FICZ) that induced M1 polarization. Chromatin immunoprecipitation confirmed AhR binding to the Il10 promoter, revealing direct transcriptional regulation. Furthermore, phthiocol reprogrammed macrophage metabolism by enhancing oxidative phosphorylation and suppressing glycolysis. These immunoregulatory and metabolic effects were abrogated by an AhR antagonist, confirming AhR dependency. Notably, phthiocol exerted similar immunoregulatory effects in activated human monocyte-derived dendritic cells and macrophages, indicating translational potential. Together, these findings position phthiocol as a selective AhR ligand with therapeutic promise for controlling inflammation and restoring immune homeostasis in inflammatory diseases.

The mRNA vaccine platform holds a great promise as novel tuberculosis vaccine. In this study, the use of mRNA encoding Ag85B from M. tuberculosis (M. tb) formulated in lipid nanoparticle (LNP) was investigated as a standalone vaccine or a booster dose for BCG in mice. Two doses of Ag85 B mRNA/LNP induced robust specific humoral response and Th1 response as measured by IFN-γ-producing T cells and polyfunctional CD8⁺ T cells (IFN-γ, TNF-α, and IL-2) in spleens and lungs. A heterologous BCG prime and mRNA/LNP boost regimen induced higher response to broad M. tb antigens than one dose of BCG vaccine or homologous prime-boost regimen by mRNA/LNP. This approach produced the highest IFN-γ-producing T cells and polyfunctional CD4⁺ T cells, indicating that mRNA/LNP provided help that enhanced the response to other antigens beyond Ag85B. The mycobacterial growth inhibition assay showed that the heterologous prime boost effectively reduced mycobacterial growth to the lowest level among the groups tested in this study. Thus, by integrating the mRNA vaccine platform into the tuberculosis vaccine development, it may be possible to provide an effective strategy to control tuberculosis.

Asiatic acid (AA) has neuroprotective potential for prevention and treatment of Alzheimer's disease. Natural waxes with various ratios of Tween 80 and Span 80 or soybean lecithin were formulated to obtain AA-loaded solid lipid nanoparticles (AA-SLN) to improve direct nose to brain transport. Optimal AA-SLN had particle size below 200 nm with uniform size distribution and zeta potential of nearly -30 mV indicating a low risk of particle aggregation. Formulation with rice bran wax, Tween 80, and soybean lecithin (AA-RwS₁₀₀) showed the highest entrapment efficiency and yield of >98 % while in vitro AA release of AA-SLN was linearly up to 48 h For ex vivo permeation, confocal laser scanning microscopy (CLSM) and histopathological studies on porcine olfactory mucosa (OM) and respiratory mucosa (RM), AA-SLN showed significantly higher permeation across OM than RM (p < 0.05) up to 6 h and AA-RwS100 also showed the highest amount of drug permeated as confirmed by CLSM results. Although AA-SLN showed non-significantly lower permeation than AA solution (AA-SOL) (p > 0.05), no epithelial and mucosal structure damages were observed in OM treated with AA-RwS₁₀₀ and RM treated with all AA-SLNs indicating safety for nasal administration while AA-SOL showed significant damage to both OM and RM. In addition, in vivo brain distribution study by fluorescence imaging using Rhodamine (R6g) showed higher brain distribution after intranasal administration of R6g-loaded solid lipid nanoparticles (R6g-SLN) than R6g solution (R6g-SOL) and intravenous administration of R6g-SLN, and R6g-RwS₁₀₀ also showed the highest brain accumulation at 8 h post administration.