Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Multiple sclerosis (MS) involve activation of glial cells and release of inflammatory mediators leading to death of neurons. Glia maturation factor (GMF) is up-regulated in the central nervous system (CNS) in these neurodegenerative diseases. Interleukin-33 (IL-33) is highly expressed constitutively in the CNS. We have treated mouse astrocytes, mixed culture with glial cells and neurons, and only neurons with GMF and/or IL-33 in vitro. Both GMF and IL-33-induced chemokine (C-C motif) ligand 2 (CCL2) release in a dose and time-dependent manner. We report that GMF induced IL-33 release, and that IL-33 augments GMF-induced TNF-α release from mouse astrocytes. IL-33 induces CCL2, TNF-α and nitric oxide release through phosphorylation of ERK in mouse astrocytes. Incubation of mixed culture containing glial cells and neurons or only neuronal culture with IL-33 reduced the number of neurons positive for microtubule-associated protein 2. In conclusion, IL-33 augments GMF-mediated neuroinflammation and may provide a new drug target for neurodegenerative and autoimmune diseases.

Design of novel nanoplatforms with single imaging elements for dynamic and enhanced T1/T2‐weighted magnetic resonance (MR) imaging of diseases still remains significantly challenging. Here, a facile strategy to synthesize light‐addressable ultrasmall Fe3O4 nanoparticles (NPs) that can form nanoclusters (NCs) under laser irradiation for enhanced and dynamic T1/T2‐weighted MR imaging of inflammatory arthritis is reported. Citric acid‐stabilized ultrasmall Fe3O4 NPs synthesized via a solvothermal approach are linked with both the arthritis targeting ligand folic acid (FA) and light‐addressable unit diazirine (DA) via polyethylene glycol (PEG) spacer. The formed ultrasmall Fe3O4‐PEG‐(DA)‐FA NPs are cytocompatible, display FA‐mediated targeting specificity to arthritis‐associated macrophage cells, and can form NCs upon laser irradiation to have tunable r1 and r2 relaxivities by varying the laser irradiation duration. With these properties owned, the designed Fe3O4‐PEG‐(DA)‐FA NPs can be used for T1‐weighted MR imaging of arthritis without lasers and enhanced dual‐mode T1/T2‐weighted MR imaging of arthritis under laser irradiation due to the formation of NCs that have extended accumulation within the arthritis region and limited intravasation back to the blood circulation. The designed light‐addressable Fe3O4‐PEG‐(DA)‐FA NPs may be used as a promising platform for dynamic and precision T1/T2‐weighted MR imaging of other diseases.

Inflammatory responses are increasingly implicated in the pathogenesis of neurodegenerative diseases such as in Alzheimer’s disease (AD). Interleukin-33 (IL-33), a member of IL-1 family, is constitutively expressed in the central nervous system and thought to be an important mediator of glial cell response to neuropathological lesions. Proinflammatory molecules are highly expressed at the vicinity of amyloid plaques (APs) and neurofibrillary tangles (NFTs), the hallmarks of AD pathology. We have investigated the expression of IL-33 and ST2 in relation to APs and NFTs in human AD and non-AD control brains by immunohistochemistry. Sections from the entorhinal cortex, where APs and NFTs appear in early stages of AD, were used for immunohistochemistry. Mouse primary astrocytes were cultured and incubated with amyloid-β1–42 (Aβ1–42), component of plaque for 72 h and analyzed for the expression of IL-33 by flow cytometry. We found strong expression of IL-33 and ST2 in the vicinity of Aβ and AT8 labelled APs and NFTs respectively, and in the glial cells in AD brains when compared to non-AD control brains. IL-33 and ST2 positive cells were also significantly increased in AD brains when compared to non-AD brains. Flow cytometric analysis revealed incubation of mouse astrocytes with Aβ1–42 increased astrocytic IL-33 expression in vitro. These results suggest that IL-33, an alamin cytokine, may induce inflammatory molecule release from the glial cells and may play important role in the pathogenesis of AD.

Development of cost-effective and highly efficient nanoprobes for targeted tumor single-photon emission computed tomography (SPECT)/computed tomography (CT) dual-mode imaging remains a challenging task. Here, multifunctional dendrimer-entrapped gold nanoparticles (Au DENPs) modified with folic acid (FA) and labeled with (99m)Tc were synthesized for targeted dual-mode SPECT/CT imaging of tumors. Generation 2 (G2) poly(amidoamine) (PAMAM) dendrimers (G2-NH2) conjugated with cyclic diethylenetriamine pentaacetic anhydride (cDTPAA) via an amide linkage and FA via a spacer of polyethylene glycol (PEG) were used for templated synthesis of Au core NPs, followed by labeling of (99m)Tc via chelation. The thus created multifunctional Au DENPs were well-characterized. It is shown that particles with an average Au core diameter of 1.6 nm can be dispersed in water, display stability under different conditions, and are cytocompatible in the studied concentration range. Further results demonstrate that the multifunctional nanoprobe is able to be utilized for targeted SPECT/CT dual-mode imaging of cancer cells having FA receptor (FAR)-overexpression in vitro and the established subcutaneous tumor model in vivo within a time frame up to 4 h. The formed multifunctional Au DENPs synthesized using dendrimers of low-generation may be employed as an effective and economic nanoprobe for SPECT/CT imaging of different types of FAR-expressing tumors.