Retinoblastoma (RB) is prone to delayed diagnosis or treatment and has an increased likelihood of metastasizing. Thus, it is crucial to perform an effective imaging examination and provide optimal treatment of RB to prevent metastasis. Nanoparticles that support diagnostic imaging and targeted therapy are expected to noninvasively integrate tumor diagnosis and treatment. Herein, we report a multifunctional nanoparticle for multimodal imaging-guided low-intensity focused ultrasound (LIFU)/immunosynergistic RB therapy. Magnetic hollow mesoporous gold nanocages (AuNCs) conjugated with Fe3O4 nanoparticles (AuNCs–Fe3O4) were prepared to encapsulate muramyl dipeptide (MDP) and perfluoropentane (PFP). The multimodal imaging capabilities, antitumor effects, and dendritic cell (DC) activation capacity of these nanoparticles combined with LIFU were explored in vitro and in vivo. The biosafety of AuNCs–Fe3O4/MDP/PFP was also evaluated systematically. The multifunctional magnetic nanoparticles enhanced photoacoustic (PA), ultrasound (US), and magnetic resonance (MR) imaging in vivo and in vitro, which was helpful for diagnosis and efficacy evaluation. Upon accumulation in tumors via a magnetic field, the nanoparticles underwent phase transition under LIFU irradiation and MDP was released. A combined effect of AuNCs–Fe3O4/MDP/PFP and LIFU was recorded and verified. AuNCs–Fe3O4/MDP/PFP enhanced the therapeutic effect of LIFU and led to direct apoptosis/necrosis of tumors, while MDP promoted DC maturation and activation and activated the ability of DCs to recognize and clear tumor cells. By enhancing PA/US/MR imaging and inhibiting tumor growth, the multifunctional AuNC–Fe3O4/MDP/PFP nanoparticles show great potential for multimodal imaging-guided LIFU/immunosynergistic therapy of RB. The proposed nanoplatform facilitates cancer theranostics with high biosafety.

Uveitis is characterized as a common cause of blindness worldwide. Aryl hydrocarbon receptor (AhR), a ligand-activated nuclear receptor, has been implicated to play a role in human uveitis, although the exact mechanisms remain poorly understood. The purpose of this study was to enhance our knowledge concerning the role of AhR during intraocular inflammation. We immunized wild-type and AhR-knockout C57BL/6J mice with IRBP651–670 to induce experimental autoimmune uveitis (EAU). Disease severity was evaluated with both clinical and histopathological grading. Blood–retinal barrier (BRB) integrity was tested by Evans blue and tight junction proteins qualifications. Apoptosis was measured using TdT-mediated dUTP nick end labeling staining. Macrophage/microglia activation and polarization were studied by immunofluorescence and Western blot. Following EAU induction, AhR−/− mice had more severe clinical and histopathological manifestations of uveitis than AhR+/+ mice. Increased vascular permeability and apoptotic cells were observed in AhR−/− EAU mice when compared with AhR+/+ EAU mice. In addition, AhR−/− EAU mice showed evidence of a significantly increased macrophage/microglia cells and a stronger polarization from the M2 to the M1 phenotype as compared to AhR+/+ EAU mice. The levels of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were increased in AhR−/− EAU mice, which was associated with the activation of NF-κB and signal transducers and activators of transcription (STAT) pathways. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an agonist of AhR, caused a significant decrease in the clinical and histopathological manifestations, preserved BRB integrity, reduced apoptotic cells, inhibited macrophage/microglia activation, and shifted their polarization from M1 toward M2. Moreover, decreased expression of pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β and inhibition of NF-κB and STAT pathways were found in EAU mice following TCDD treatment. In conclusion, AhR activation with TCDD exhibits an immunomodulatory effect by reducing BRB breakdown, inhibiting retinal cell apoptosis, and reducing pro-inflammatory cytokine expression during EAU. The underlying mechanism may involve the modulation of macrophages/microglia polarization and the downregulation of NF-κB and STAT pathways.

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Researches have been focusing on the role of Slit2 in angiogenesis, specifically in cell migration and vessel permeability. Nevertheless, the role of Slit2-N, the bioactive fragment of Slit2, in the proliferation of vascular endothelia in choroidal neovascularization and some related mechanisms have not been studied yet. Thus, our study aimed to explore the role of Slit2-N in proliferation of vascular endothelia and the related mechanisms in choroidal neovascularization. Fluorescein isothiocyanate perfusion and HE staining were performed to evaluate volumes of choroidal neovascularization lesions. The effect of Slit2-N on VEGF165-induced cell proliferation and some related mechanisms were detected by CCK8 assay, flow cytometry, siRNA transfection, and western blotting. We found that Slit2-N reduced volumes of laser-induced choroidal neovascularization networks in vivo. Results of the in vitro study showed Slit2-N reduced VEGF165-induced cell proliferation of both human umbilical vascular endothelial cells and human microvascular endothelial cells possibly via activation of AKT rather than that of ERK1/2. Additionally, Robo4, one of the receptors binding to Slit2-N, was involved in the inhibitory effect of Slit2-N. Generally, our findings revealed the inhibitory role of Slit2-N in proliferation of vascular endothelia and some related mechanisms, and presented some potential targets, molecules along Slit2-N-Robo4-AKT axis, to choroidal neovascularization therapy.

YKL-40 serum levels may contribute to wet age-related macular degeneration via the ERK1/2 pathway Running head: YKL-40 and wet age-related macular degeneration