PSMC5 regulates microglial polarization and activation in LPS-induced cognitive deficits and motor impairments by interacting with TLR4.

Luteolin is a flavonoid found in high concentrations in celery and green pepper, and acts as a neuroprotectant. PSMC5 (proteasome 26S subunit, ATPase 5) protein levels were reduced after luteolin stimulation in activated microglia. We aimed to determine whether regulating PSMC5 expression could inhibit neuroinflammation, and investigate the underlying mechanisms.BV2 microglia were transfected with siRNA PSMC5 before the addition of LPS (lipopolysaccharide, 1.0 µg/ml) for 24 h in serum free DMEM. A mouse model of LPS-induced cognitive and motor impairment was established to evaluate the neuroprotective effects of shRNA PSMC5. Intracerebroventricular administration of shRNA PSMC5 was commenced 7 days prior to i.p. injection of LPS (750 µg/kg). Treatments and behavioral experiments were performed once daily for 7 consecutive days. Behavioral tests and pathological/biochemical assays were performed to evaluate LPS-induced hippocampal damage. Molecular dynamics simulation was used to confirm the interaction between PSMC5 and TLR4 (Toll-like receptor 4) in LPS-stimulated BV2 microglia. SiRNA PSMC5 inhibited BV2 microglial activation, and suppressed the release of inflammatory factors (IL-1ß, COX-2, PGE2, TNF-α, and iNOS) upon after LPS stimulation in BV2 microglia. LPS increased IκB-α and p65 phosphorylation, which was attenuated by siRNA PSMC5. Behavioral tests and pathological/biochemical assays showed that shRNA PSMC5 attenuated LPS-induced cognitive and motor impairments, and restored synaptic ultrastructure and protein levels in mice. ShRNA PSMC5 reduced pro-inflammatory cytokine (TNF-α, IL-1ß, PGE2, and NO) levels in the serum and brain, and relevant protein factors (iNOS and COX-2) in the brain. Furthermore, shRNA PSMC5 upregulated the anti-inflammatory mediators interleukin IL-4 and IL-10 in the serum and brain, and promoted a pro-inflammation-to-anti-inflammation phenotype shift in microglial polarization. Mechanistically, shRNA PSMC5 significantly alleviated LPS-induced TLR4 expression. The polarization of LPS-induced microglial pro-inflammation phenotype was abolished by TLR4 inhibitor and in the TLR-4-/- mouse, as in shRNA PSMC5 treatment. PSMC5 interacted with TLR4 via the amino sites Glu284, Met139, Leu127, and Phe283. PSMC5 site mutations attenuated neuroinflammation and reduced pro-inflammatory factors by reducing TLR4-related effects, thereby reducing TLR4-mediated MyD88 (myeloid differentiation factor 88)-dependent activation of NF-κB. PSMC5 could be an important therapeutic target for treatment of neurodegenerative diseases involving neuroinflammation-associated cognitive deficits and motor impairments induced by microglial activation.

Dietary Copper Intake and Risk of Parkinson's Disease: a Cross-sectional Study.

Copper is an essential trace element for the human body. The epidemiological evidence for the association of dietary intake of copper with the risk of Parkinson's disease (PD) is limited. We conducted an evaluation of the cross-sectional data gathered from the National Health and Nutrition Examination Surveys spanning from 2007 to 2018, which comprised a total of 17,948 participants. To discern the distinct characteristics of the participants, we performed a univariate analysis and utilized a 1:2 ratio propensity score matching method to minimize the effects of selection bias. We employed weighted univariate as well as three multivariate logistic regression models both prior to and following matching, with the aim of examining the association between dietary copper intake and PD risk. Finally, we used the restricted cubic spline (RCS) methodology in order to investigate possible non-linear relationships. Furthermore, subgroup analysis was undertaken to elicit further understanding concerning the association between copper intake and PD. A negative correlation resulted between dietary copper intake and PD risk in both univariate and multivariate logistic regression models, prior to and following matching. Our findings demonstrate that there is a nonlinear, dose-dependent relationship between copper intake and PD, according to our RCS analysis. In subgroup analysis, copper intake was identified as an important protective factor for individuals who were non-Hispanic White, unmarried, and had completed higher education. Dietary copper intake was associated with the risk of PD. Supplementation of dietary copper may have potentially beneficial effects.

Correlations Between Dietary Magnesium Consumption and Magnesium Depletion Score in Relation to Parkinson's Disease: A Population-Based Study.

The purpose of the study was to examine whether magnesium (Mg) depletion score (MDS) and dietary Mg intake are associated in adults with the risk of developing Parkinson's disease (PD). In this study, we analyzed data from the National Health and Nutrition Examination Survey (NHANES), which included 20,010 adults aged over 40 years old. To evaluate the linear association between PD and dietary intake of Mg or MDS, we conducted weighted logistic regression for univariate analysis and multivariate linear regression models. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression models. A restricted cubic spline (RCS) was drawn to visualize the nonlinear relationship between MDS/dietary Mg intake and PD. In addition, we examined the variations in the relationship between MDS and PD across different confounding factors of the association using subgroup analysis. There were 240 PD cases (1.2%), and 19770 non-PD were included in the study. We found that a higher MDS was associated with an increased risk of PD after adjusting for covariates (OR per 1-unit increase, 1.47; 95% CI, 1.16-1.86). There is insufficient evidence to support a significant statistical association between Mg intake and the risk of PD. According to nonlinear regression, high MDS was associated with higher odds of PD and lower odds of PD above 250 mg/day intake of Mg. It has been shown that Mg bioavailability may be negatively associated with PD as measured by MDS. MDS is a potential method for screening the population with PD. Maintaining adequate Mg status may be important for PD prevention.

Association between blood selenium with parkinson's disease in the US (NHANES 2011-2020).

Selenium is an essential trace element for human health, playing a key role in regulating cellular oxidative stress, immune response, and inflammation. In recent years, the association between selenium and Parkinson's disease (PD) has aroused people's attention. The objective of this study is to investigate the relationship between blood selenium concentrations and PD risk in a sample of U.S. adults. A cross-sectional study was conducted using the National Health and Nutrition Examination Survey (NHANES) data from 2011-2020 and included 15,660 adults aged over 40 years old. Univariate logistic regression and multivariate logistic regression models were utilized to analyze the association between blood selenium concentrations and PD prevalence. Additionally, the restricted cubic spline (RCS) model was applied to investigate the dose-response relationships between blood selenium and PD. The findings indicated a link between elevated blood selenium levels and a reduced occurrence of Parkinson's disease (PD). Notably, this association between blood selenium and PD exhibited a non-linear pattern, wherein the decline in PD risk was more pronounced at higher selenium concentrations than at lower levels. An inflection point emerged at approximately 2.4 µmol/L, beyond which the rate of decline in risk significantly diminished with increasing selenium levels. A potential association between blood selenium concentrations and PD has been observed, with PD patients having lower blood selenium levels compared to non-PD patients. Higher levels of blood selenium may have a protective effect against PD. However, further prospective studies are needed to investigate the effect of blood selenium in PD patients and to determine causality.

Association between dietary inflammatory index and Parkinson's disease from National Health and Nutrition Examination Survey (2003-2018): a cross-sectional study.

Objected: To explore the association between Parkinson's disease (PD) and dietary inflammatory index (DII) scores in adults over 40 years old in the US. Method: Data were collected from the National Health and Nutrition Examination Survey (NHANES) conducted from 2003 to 2018. A total of 21,994 participants were included in the study. A weighted univariate and multivariable logistic regression analysis was performed to investigate the association between the DII and PD, in which continuous variables or categorical variables grouped by tertiles was used. The relationship between DII and PD has been further investigated using propensity score matching (PSM) and a subgroup analysis stratified based on DII and PD characteristics. Moreover, restricted cubic spline (RCS) analysis was conducted to examine whether there was a nonlinear association between DII and PD. Results: A total of 21,994 participants were obtained for statistical analysis, made up of 263 patients with PD and 21,731 participants without PD. Univariate and multivariable logistics regression analysis showed DII to be positively associated with PD before and after matching. Subgroup analysis revealed a statistical difference in non-Hispanic whites, but RCS analysis suggested that there was no nonlinear relationship between the DII and PD. Conclusion: For participants over 40 years of age, higher DII scores were positively correlated with PD. In addition, these results support the ability of diet to be used as an intervention strategy for managing PD.

Elevated visceral adiposity index linked to improved cognitive function in middle-aged and elderly Chinese: evidence from the China health and retirement longitudinal study.

Object: Cognitive decline and obesity are major global public health issues, and their association has been widely acknowledged. The link between the visceral adiposity index (VAI) and cognitive function in the Chinese population remains uncertain. This study aims to investigate the effects of VAI levels on cognitive function in the Chinese middle-aged and elderly population. Methods: We analyzed longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS) collected in 2011, 2013, 2015, and 2018. VAI levels were divided into three tertiles. Generalized estimating equation (GEE) models were used to explore the relationships between VAI levels and cognitive function, including overall cognitive scores, episodic memory, and mental status. Adjustments were made for potential confounders. Results: The study consisted of 2,677 participants. Contrary to expectations, higher VAI levels were associated with higher overall cognitive scores and improved episodic memory scores, while no significant effect was observed on mental status. The GEE models consistently indicated that higher VAI levels were associated with higher overall cognitive scores, primarily due to their association with episodic memory. Stratified analyses revealed that the VAI was associated with better cognitive function primarily in males, individuals under 60 years old, those with lower education levels, rural residents, and married individuals, mainly in relation to episodic memory. No significant interactions were observed between VAI and demographic factors. Conclusion: Our findings suggest that higher visceral adiposity is associated with slower cognitive decline in the Chinese middle-aged and elderly population, especially in its association with episodic memory. These results underline the need to further investigate the potential protective role of visceral fat in cognitive function, potentially offering new insights for interventions to enhance cognitive function and prevent dementia in this population.