Background: Experimental autoimmune encephalomyelitis (EAE) is the most common animal model of multiple sclerosis (MS), a neuroinflammatory and demyelinating disease characterized by multifocal perivascular infiltrates of immune cells. Although EAE is predominantly considered a T helper 1-driven autoimmune disease, mounting evidence suggests that activated dendritic cells (DC), which are the bridge between innate and adaptive immunity, also contribute to its pathogenesis. Sirtuin 6 (SIRT6), a NAD⁺-dependent deacetylase involved in genome maintenance and in metabolic homeostasis, regulates DC activation, and its pharmacological inhibition could, therefore, play a role in EAE development.Methods: EAE was induced in female C57bl/6 mice by MOG35-55 injection. The effect of treatment with a small compound SIRT6 inhibitor, administered according to therapeutic and preventive protocols, was assessed by evaluating the clinical EAE score. SIRT6 inhibition was confirmed by Western blot analysis by assessing the acetylation of histone 3 lysine 9, a known SIRT6 substrate. The expression of DC activation and migration markers was evaluated by FACS in mouse lymph nodes. In addition, the expression of inflammatory and anti-inflammatory cytokines in the spinal cord were assessed by qPCR. T cell infiltration in spinal cords was evaluated by immunofluorescence imaging. The effect of Sirt6 inhibition on the migration of resting and activated bone marrow-derived dendritic cells was investigated in in vitro chemotaxis assays.Results: Preventive pharmacological Sirt6 inhibition effectively delayed EAE disease onset through a novel regulatory mechanism, i.e., by reducing the representation of CXCR4-positive and of CXCR4/CCR7-double-positive DC in lymph nodes. The delay in EAE onset correlated with the early downregulation in the expression of CD40 on activated lymph node DC, with increased level of the anti-inflammatory cytokine IL-10, and with a reduced encephalitogenic T cell infiltration in the central nervous system. Consistent with the in vivo data, in vitro pharmacological Sirt6 inhibition in LPS-stimulated, bone marrow-derived DC reduced CCL19/CCL21- and SDF-1-induced DC migration.Conclusions: Our findings indicate the ability of Sirt6 inhibition to impair DC migration, to downregulate pathogenic T cell inflammatory responses and to delay EAE onset. Therefore, Sirt6 might represent a valuable target for developing novel therapeutic agents for the treatment of early stages of MS, or of other autoimmune disorders.

In the last decade, many small molecules, usually characterized by heterocyclic scaffolds, have been designed and synthesized as tyrosine kinase inhibitors (TKIs). Among them, several compounds have been tested at preclinical and clinical levels to treat glioblastoma multiforme (GBM). GBM is the most common and aggressive type of cancer originating in the brain and has an unfavorable prognosis, with a median survival of 15–16 months and a 5-year survival rate of 5%. Despite recent advances in treating GBM, it represents an incurable disease associated with treatment resistance and high recurrence rates. For these reasons, there is an urgent need for the development of new pharmacological agents to fight this malignancy. In this review, we reported the compounds published in the last five years, which showed promising activity in GBM preclinical models acting as TKIs. We grouped the compounds based on the targeted kinase: first, we reported receptor TKIs and then, cytoplasmic and peculiar kinase inhibitors. For each small molecule, we included the chemical structure, and we schematized the interaction with the target for some representative compounds with the aim of elucidating the mechanism of action. Finally, we cited the most relevant clinical trials.

Chitosan–hydroxyapatite (CS-HAp) biocomposites, combining the biocompatibility and bioactivity of chitosan with the osteoconductive properties of hydroxyapatite, are emerging as promising candidates for tissue engineering applications. These materials consistently exhibit excellent cytocompatibility, with cell viability rates greater than 95% in MTT and Neutral Red Uptake assays, and minimal cytotoxicity, as demonstrated by low levels of cell death in DAPI and Trypan blue staining. More importantly, CS-HAp biocomposites modulate the immune environment by enhancing the expression of anti-inflammatory cytokines (IL-10 and IL-4) and the pro-inflammatory cytokine TGF-β, while avoiding significant increases in TNF-α, IL-6, or NF-κB expression in fibroblast cells exposed to HAC and HACF scaffolds. In an in vivo dermatitis model, these biocomposites reduced mast cell counts and plasma histamine levels and significantly decreased pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), JAK1/3, VEGF, and AnxA1 levels. Structurally, HACF scaffolds demonstrated larger average pore sizes (95 µm) compared to HAC scaffolds (74 µm), with porosities of 77.37 ± 2.4% and 65.26 ± 3.1%, respectively. These materials exhibited high swelling ability, equilibrium water content, and controlled degradation over a week in culture media. In addition to their immunomodulatory effects, CS-HAp composites promote essential cellular activities, such as attachment, proliferation, and differentiation, thereby supporting tissue integration and healing. Despite these promising findings, significant gaps remain in understanding the underlying mechanisms of immune modulation by CS-HAp biocomposites, and formulation-dependent variability raises concerns about reproducibility and clinical application. Therefore, a comprehensive review is essential to consolidate existing data, identify key knowledge gaps, and standardize the design of CS/HAp composites for broader clinical use, particularly in immunomodulatory and regenerative medicine contexts.