Alzheimer’s disease (AD) is thought to be a series of neuroinflammatory diseases caused by abnormal deposits of amyloid-β (Aβ) and tau protein in the brain as part of its etiology. We focused on Aβ aggregation and M1 and M2 microglial polarity in microglia to search for novel therapeutic agents. It has been reported that the inhibition of choline uptake via choline transporter-like protein 1 (CTL1) in microglia preferentially induces M2 microglial polarity. However, the role of the choline transport system on the regulation of microglial M1/M2 polarity in AD is not fully understood. Licochalcones (Licos) A–E, flavonoids extracted from licorice, have been reported to have immunological anti-inflammatory effects, and Lico A inhibits Aβ aggregation. In this study, we compared the efficacy of five Licos, from Lico A to E, at inhibiting Aβ1-42 aggregation. Among the five Licos, Lico E was selected to investigate the relationship between the inhibition of choline uptake and microglial M1/M2 polarization using the immortalized mouse microglial cell line SIM-A9. We newly found that Lico E inhibited choline uptake and Aβ1-42 aggregation in SIM-A9 cells in a concentration-dependent manner, suggesting that the inhibitory effect of Lico E on choline uptake is mediated by CTL1. The mRNA expression of tumor necrosis factor (TNF-α), a marker of M1 microglia, was increased by Aβ1-42, and its effect was inhibited by choline deprivation and Lico E in a concentration-dependent manner. In contrast, the mRNA expression of arginase-1 (Arg-1), a marker of M2 microglia, was increased by IL-4, and its effect was enhanced by choline deprivation and Lico E. We found that Lico E has an inhibitory effect on Aβ aggregation and promotes polarity from M1 to M2 microglia via inhibition of the CTL1 function in microglia. Thus, Lico E may become a leading compound for a novel treatment of AD.

Background/Objectives: Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated host response to infection. Mitochondrial dysfunction is considered a key contributor to the pathogenesis of sepsis, but its molecular mechanisms remain unclear. Methods: In this study, we used a cecal ligation and puncture (CLP) model to induce sepsis in wild-type (WT) and cyclophilin D knockout (CypD KO) mice. Liver tissues were collected at 0, 6, and 18 h post-CLP and analyzed using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Results: Metabolomic profiling revealed that lactate levels significantly increased in the WT mice but remained stable in the KO mice. While AMP levels were preserved in the KO mice, these mice had significantly higher glutathione disulfide (GSSG) and spermidine concentrations than the WT mice at 18 h (p < 0.05). The levels of malondialdehyde (MDA), a marker of oxidative stress, were also significantly lower in the KO mice at 18 h (p < 0.05). These findings suggest that CypD deficiency preserves mitochondrial function, enhances resistance to oxidative stress, and mitigates septic liver injury. Conclusions: Our results highlight the potential of targeting mitochondrial permeability transition as a therapeutic strategy for sepsis.

Background/Objectives: In recent years, it has been suggested that sedatives may cause brain damage. One possible mechanism is interference with oxidative phosphorylation of brain mitochondria, but much remains unknown. In this study, we focused on dexmedetomidine, midazolam, and propofol, essential sedatives in anesthesia and intensive care, and aimed to understand the effects of these drugs on mouse brain mitochondria. Methods: We measured changes in mitochondrial respiratory capacity and swelling rate upon exposure to these sedatives in a wide concentration range. For the sedative that demonstrated impaired mitochondrial function we explored the possible involvement of mitochondrial permeability transition pore opening using brain mitochondria from cyclophilin D knockout (CypD KO) mice and detected cytochrome c (cyt c) release by Western blot. Results: Of the three sedatives, only high concentrations of propofol exhibited reduced respiratory capacity and mitochondrial swelling, toxicity which was not prevented by CypD KO. Furthermore, propofol did not induce cyt c release. Conclusions: These results suggest that propofol-induced brain mitochondrial dysfunction is a mechanism independent of mPTP opening.