FoxO1 Alleviates the Mitochondrial ROS Levels Induced by α-Synuclein Preformed Fibrils in BV-2 Microglial Cells.

Parkinson's disease (PD) is a complex neurodegenerative disorder marked by the gradual deterioration of dopaminergic neurons, especially in the substantia nigra pars compacta (SNc). Dysregulation of the transcription factor FoxO1 is associated with various neurodegenerative conditions, including Alzheimer's disease and PD, though the specific mechanisms involved are not fully understood. This study explores the effects of α-Synuclein preformed fibrils (PFF) on BV-2 microglial cells, focusing on changes in molecular characteristics and their impact on neuronal degeneration. Our results demonstrate that PFF treatment significantly increases FoxO1 mRNA (p = 0.0443) and protein (p = 0.0216) levels, leading to its nuclear translocation (p = 0.0142) and enhanced expression of genes involved in the detoxification of reactive oxygen species (ROS), such as Catalase (Cat, p = 0.0249) and superoxide dismutase 2 (Sod2, p = 0.0313). Furthermore, we observed that PFF treatment elevates mitochondrial ROS levels. However, cells lacking FoxO1 or treated with FoxO1 inhibitors showed increased vulnerability to PFF-induced ROS, attributed to reduced expression of ROS detoxifying enzymes Cat and Sod2 (p < 0.0001). Besides enhancing ROS production, inhibiting FoxO1 also heightens neurotoxicity induced by PFF treatment in microglia-conditioned medium (p < 0.0001). Conversely, treatment with N-acetylcysteine or bacterial superoxide dismutase A mitigated the ROS increase induced by PFF (p < 0.0001). These findings suggest the essential role of FoxO1 in regulating ROS levels, which helps alleviate pathology in PFF-induced PD models. Our study provides insights into the genetic mechanisms of PD and suggests potential pathways for developing novel therapeutic strategies.

Preclinical and Preliminary Evaluation of Perceived Image Quality of AI-Processed Low-Dose CBCT Analysis of a Single Tooth.

This study assessed AI-processed low-dose cone-beam computed tomography (CBCT) images for single-tooth diagnosis. Human-equivalent phantoms were used to evaluate CBCT image quality with a focus on the right mandibular first molar. Two CBCT machines were used for evaluation. The first CBCT machine was used for the experimental group, in which images were acquired using four protocols and enhanced with AI processing to improve quality. The other machine was used for the control group, where images were taken in one protocol without AI processing. The dose-area product (DAP) was measured for each protocol. Subjective clinical image quality was assessed twice by five dentists, with a 2-month interval in between, using 11 parameters and a six-point rating scale. Agreement and statistical significance were assessed with Fleiss' kappa coefficient and intra-class correlation coefficient. The AI-processed protocols exhibited lower DAP/field of view values than non-processed protocols, while demonstrating subjective clinical evaluation results comparable to those of non-processed protocols. The Fleiss' kappa coefficient value revealed statistical significance and substantial agreement. The intra-class correlation coefficient showed statistical significance and almost perfect agreement. These findings highlight the importance of minimizing radiation exposure while maintaining diagnostic quality as the usage of CBCT increases in single-tooth diagnosis.

DJ-1 protects cell death from a mitochondrial oxidative stress due to GBA1 deficiency.

BACKGROUND: GBA1 mutations are the most common genetic risk factor for development of Parkinson's disease (PD). The loss of catalytic activity in GBA1, as well as the reduction of the GBA1 protein in certain cellular compartment, may increase disease progression. However, the mechanisms underlying cellular dysfunction caused by GBA1 deficiency are still mostly unknown. OBJECTIVE: In this study, we focus on the genetic interaction between GBA1 deficiency and PD-causing genes, such as DJ-1, in mitochondrial dysfunction. METHODS: GBA1 knockout (KO) SH-SY5Y cells were used to assess DJ-1 functions against oxidative stress in vitro. The levels of cellular reactive oxygen species were monitored with MitoSOX reagent. The expression of the PARK7 gene was analyzed using the quantitative real-time PCR (qRT-PCR). To understand the mechanism underlying DJ-1 upregulation in GBA1 KO cells, we assess ROS levels, antioxidant protein, and cell viability in GBA1 KO cells with treatment of ROS inhibitor N-acetyl-cysteine or miglustat, which is an inhibitor of glucosylceramide synthase. Dopaminergic degeneration was assessed from Gba1 L444P heterozygous mice mated with Park7 knockout mice. RESULTS: We find that DJ-1 is significantly upregulated in GBA1 KO cells. Elevated levels of DJ-1 are attributed to the transcriptional expression of PARK7 mRNA, but not the inhibition of DJ-1 protein degradation. Because DJ-1 expression is highly linked to oxidative stress, we observe cellular reactive oxygen species (ROS) in GBA1 KO cells. Moreover, several antioxidant gene expressions and protein levels are increased in GBA1 KO cells. To this end, GBA1 KO cells are more susceptible to H2O2-induced cell death. Importantly, there is a significant reduction in dopaminergic neurons in the midbrain from Gba1 L444P heterozygous mice mated with Park7 knockout mice, followed by mild motor dysfunction. CONCLUSION: Taken together, our results suggest that DJ-1 upregulation due to GBA1 deficiency has a protective role against oxidative stress. It may be supposed that mutations or malfunctions in the DJ-1 protein may have disadvantages in the survival of dopaminergic neurons in the brains of patients harboring GBA1 mutations.

Why People Trust Something Other than Science: Cases of Acupuncture and Four Pillars of Destiny in Korea.

In modern society, people are expected to make scientific decisions and rational actions over a range of personal and social problems. There have been a number of studies on students' and adults' decision-making over socio-scientific issues under the name of scientific literacy. In this study, we investigated the social and cultural backgrounds of Korean people's actions and trust over their personal problems (e.g. health, career choice), by conducting in-depth interviews with ten Korean adults on their experience related to acupuncture and Four Pillars of Destiny (FPD), two representative examples of unorthodox sciences. The analysis of the data reveals that their actions concerning acupuncture and FPD are influenced by socio-cultural factors (esp. family culture, social system) and by their understandings of the nature of science. In addition, we found that there are a different set of reasons and varying degrees of people's trust between acupuncture and FPD. Based on the results, we discussed the needs to introduce wider concepts of the nature of science and of the scopes of science education.