Monoamine oxidase–B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer’s disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC₅₀ = 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.

Anaplastic thyroid cancer (ATC), a rare thyroid cancer with poor prognosis, is associated with insufficient function of the sodium iodide symporter (NIS). Estrogen-related receptor gamma (ERRγ) is a member of the orphan nuclear receptors, with important functions in cell development and homeostasis. However, there are no reports that demonstrate whether ERRγ is related with NIS function. Here, we evaluated the role of ERRγ on the regulation of NIS function in ATC cells by using GSK5182, an inverse agonist of ERRγ. Methods: Two ATC cell lines, BHT-101 and CAL62, were incubated with the GSK5182 at various time points and dosages. Serial assessment of the NIS function was performed in the ATC cells by their uptake of radioiodine. The effects of GSK5182 on ERRγ and the mitogen-activated protein (MAP) kinase pathway as well as on NIS protein were evaluated by immunoblot assay. To examine whether the GSK5182-induced NIS functional activity can be affected by inhibition of the MAP kinase pathway, the MAP kinase activity and levels of radioiodine uptake were determined following treatment of an MEK inhibitor to GSK5182-treated cells. Finally, the cytotoxic effect of ¹³¹I was determined by clonogenic assay. Results: Treatment with GSK5182 resulted in dose- and time-dependent increases in iodide uptake in ATC cells, which were accompanied by both the down-regulation of ERRγ protein and the activation of extracellular signal-regulated kinase (ERK)-1/2. Both the increased radioiodine uptake and ERK-1/2 activation of ATC cells were completely inhibited by the specific MEK inhibitor. GSK5182 treatment enhanced the membrane localization of NIS in both ATC cells. Accordingly, pre-exposure to GSK5182 resulted in enhanced cytotoxic effects of ¹³¹I treatment in ATC cells. Conclusion: These findings suggest that the inverse agonist of ERRγ enhances the responsiveness of radioiodine therapy by modulating NIS function in ATC cells via the regulation of ERRγ and the MAP kinase signaling pathway.

Reliable and sensitive imaging tools are required to track macrophage migration and provide a better understating of their biological roles in various diseases. Here, we demonstrate the possibility of radioactive iodide-embedded gold nanoparticles (RIe-AuNPs) as a cell tracker for nuclear medicine imaging. To demonstrate this utility, we monitored macrophage migration to carrageenan-induced sites of acute inflammation in living subjects and visualized the effects of anti-inflammatory agents on this process. Macrophage labeling with RIe-AuNPs did not alter their biological functions such as cell proliferation, phenotype marker expression, or phagocytic activity. In vivo imaging with positron-emission tomography revealed the migration of labeled macrophages to carrageenan-induced inflammation lesions 3 h after transfer, with highest recruitment at 6 h and a slight decline of radioactive signal at 24 h; these findings were highly consistent with the data of a bio-distribution study. Treatment with dexamethasone (an anti-inflammation drug) or GSK5182 (an ERRγ inverse agonist) hindered macrophage recruitment to the inflamed sites. Our findings suggest that a cell tracking strategy utilizing RIe-AuNPs will likely be highly useful in research related to macrophage-related disease and cell-based therapies.

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Plasmonic nanostructure-mediated photothermal therapy (PTT) has proven to be a promising approach for cancer treatment, and new approaches for its effective delivery to tumor lesions are currently being developed. This study aimed to assess macrophage-mediated delivery of PTT using radioiodine-124-labeled gold nanoparticles with crushed gold shells (¹²⁴I-Au@AuCBs) as a theranostic nanoplatform. ¹²⁴I-Au@AuCBs exhibited effective photothermal conversion effects both in vitro and in vivo and were efficiently taken up by macrophages without cytotoxicity. After the administration of ¹²⁴I-Au@AuCB-labeled macrophages to colon tumors, intensive signals were observed at tumor lesions, and subsequent in vivo PTT with laser irradiation yielded potent antitumor effects. The results indicate the considerable potential of ¹²⁴I-Au@AuCBs as novel theranostic nanomaterials and the prominent advantages of macrophage-mediated cellular therapies in treating cancer and other diseases.