ABSTRACT
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.
ABSTRACT
This study reports the preliminary efficacy of an innovative school-based, technology-enhanced social-emotional learning program called "mindfulness-based collaborative social reasoning" (MBCSR) for middle school students. MBCSR was developed by an interdisciplinary team of educational psychologists, mindfulness researchers, computer scientists, and health experts. We integrated the strengths of contemplative approaches, collaborative small group discussions, learning technology, and multidimensional assessments of students' social-emotional outcomes. Using a quasi-experimental design, the study was implemented in four sixth-grade English language arts classrooms (2 experimental and 2 business-as-usual control; N = 74) in a public middle school in the Midwest of the United States. It was co-implemented by researchers and teachers, with sessions occurring for 45 minutes, once per week, for 8 weeks. The MBCSR group showed greater self-efficacy for using Upa-yoga and mindful breathing to regulate their emotions and behaviors ( η p 2 $$ {\eta}_p^2 $$ = .13), and lower externalizing ( η p 2 $$ {\eta}_p^2 $$ = .07) and bullying behaviors ( η p 2 $$ {\eta}_p^2 $$ = .09) at the posttest compared to the control group, after controlling for baseline differences. Students in the experimental group overall showed positive and relaxed emotional and physiological states during the sessions. There were no significant differences between the two groups in mindfulness, emotional regulation, and social skills. This program sets an example for integrating social-emotional learning and academic learning into students' daily content instruction.
ABSTRACT
There have been previous studies conducted to predict postoperative lung function with pulmonary function tests (PFTs). Computing tomography (CT) can quantitatively measure small airway walls' thickness, lung volume, pulmonary vessel volume, and emphysema area, which reflect the severity of respiratory diseases. These measurements are considered imaging biomarkers. This study aimed to predict postoperative lung function with imaging biomarkers. A retrospective analysis of 79 patients with lung cancer who had undergone lung surgery was completed. Postoperative lung function measured by forced expiratory volume in one second (FEV1) was defined as an outcome. Preoperative clinico-pathological parameters and imaging biomarkers representing airway walls' thickness, severity of emphysema, total lung volume, and pulmonary vessel volume were measured quantitatively in chest CT by an automated segmentation software, AVIEW COPD. Pi1 was defined as the first percentile along the histogram of lung attenuation that represents the degree of emphysema. Wafw was defined as the airway thickness, which was calculated by the full-width at half-maximum method. Logistic and linear regressions were used to assess these variables. If the actual postoperative FEV1 was higher than the postoperative FEV1 projected by a formula, the group was considered to be preserved. Among the 79 patients, 16 of the patients were grouped as a non-preserved group, and 63 of them were grouped as a preserved group. The patients in the preserved FEV1 group had a higher vessel volume than the non-preserved group. Pi1 and Wafw were independent predictors of postoperative lung function. Imaging biomarkers can be considered significant variables in predicting postoperative lung function in patients with lung cancer.
ABSTRACT
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.
Subject(s)
Antioxidants , Neuroblastoma , Parkinson Disease , Humans , Mice , Animals , Reactive Oxygen Species/metabolism , Antioxidants/metabolism , Hydrogen Peroxide , Oxidative Stress , Cell Death/physiology , Mice, Knockout , Protein Deglycase DJ-1/genetics , Protein Deglycase DJ-1/metabolismABSTRACT
Vasoactive intrinsic peptide receptor (VIPR2), a circadian gene, is involved in metabolic homeostasis and metabolic syndrome (MetS). Seaweeds contain polysaccharides that regulate metabolic homeostasis, possibly by altering the effects of VIPR2 variants. We examined the relationship between VIPR2 expression and the incidence of MetS based on seaweed consumption. This study included 4979 Koreans aged ≥40 years using data from the Ansan-Ansung cohort of the Korean Genome and Epidemiology Study. The total seaweeds included were laver, kelp, and sea mustard. A multivariable Cox proportional hazards model was used to analyze the interactions between the VIPR2 rs6950857 genotype associated with MetS incidence and seaweed intake after adjusting for covariates such as region. A total of 2134 patients with MetS were followed for an average of 8.9 years. In men with the GG genotype of rs6950857, the highest quintile of seaweed consumption was associated with a decreased incidence of MetS compared with that of the lowest quintile (hazard ratio, 0.78; 95% confidence interval, 0.62-0.98). We identified a unique association between the rs6950857 genotype, seaweed intake, and MetS. These findings highlight the importance of VIPR2 and the regulatory role of seaweed consumption in MetS incidence.
Subject(s)
Metabolic Syndrome , Seaweed , Male , Middle Aged , Humans , Metabolic Syndrome/epidemiology , Metabolic Syndrome/genetics , Risk Factors , Incidence , East Asian People , Vegetables , Republic of Korea/epidemiology , Receptors, Vasoactive Intestinal Peptide, Type IIABSTRACT
The present study aimed to determine a multimodal brain empowerment (MBE) program to mitigate the modifiable risk factors in mild cognitive impairment (MCI), and its therapeutic effects are unknown. MBE encompassing (1) tDCS, light therapy, computerized cognitive therapy (TLC) and (2) robot-assisted gait training, music therapy, and core exercise (REM) interventions were randomly assigned to 20 healthy young adults and 20 older adults with MCI. The electroencephalography (EEG) power spectrum and topographic event-related synchronization (ERS) analysis were used to assess intervention-related changes in neural activity during the MBE program. Outcome: The EEG results demonstrated that both multimodal TLC and REM decreased delta waves and increased theta, alpha, and beta waves (p < 0.001). ERS showed increased neural activation in the frontal, temporal, and parietal lobes during TLC and REM. Such enhanced neural activity in the region of interest supports potential clinical benefits in empowering cognitive function in both young adults and older adults with MCI.
ABSTRACT
While falls among patients with mild cognitive impairment (MCI) have been closely associated with an increased postural sway during ecological activities of daily living, there is a dearth of postural sway detection (PSD) research in ecological environments. The present study aimed to investigate the fall sensitivity, specificity, and accuracy of our PSD system. Forty healthy young and older adults with MCI at a high risk of falls underwent the sensitivity, specificity, and accuracy tests for PSD by simultaneously recording the Berg Balance Scale and Timed Up and Go in ecological environments, and the data were analyzed using the receiver operating characteristic curve and area under the curve. The fall prediction sensitivity ranged from 0.82 to 0.99, specificity ranged from 0.69 to 0.90, and accuracy ranged from 0.53 to 0.81. The PSD system's fall prediction sensitivity, specificity, and accuracy data suggest a reasonable discriminative capacity for distinguishing between fallers and non-fallers as well as predicting falls in older adults with MCI in ecological testing environments.
Subject(s)
Activities of Daily Living , Cognitive Dysfunction , Humans , Aged , Postural Balance , Cognitive Dysfunction/diagnosis , ROC CurveABSTRACT
BACKGROUND: Reduced meal frequency can increase the risk of metabolic syndrome (MetS). However, limited studies have examined the association between meal frequency and skipping meals with MetS. This study aims to analyze the association between main meal frequency and meal skipping with MetS in Korean adults aged ≥ 19 years. METHODS: In this study, we included data from 22,699 Korean adult participants from the 2016-2020 Korea National Health and Nutrition Examination Survey (KNHANES). The 24-h dietary recall method was used to classify the participants into three groups based on main meal frequency (one, two, or three meals per day) and seven groups based on the type of main meal they skipped. Multivariable logistic regression analysis was conducted to determine the association between main meal frequency and the types of main meals skipped with the odds of MetS and its associated components. Appropriate estimates were accounted for using sampling weights, stratification, and clustering. RESULTS: The prevalence of MetS in the study population was 33.8%. The average age of the participants was 47.2 years with 42.6% being men, and 57.4% being women. Men who consumed two meals per day had higher odds of MetS than those who consumed three meals per day (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.01-1.33). Women who consumed two meals per day, and skipped breakfast had increased odds of having elevated fasting blood glucose levels (OR 1.18, 95% CI 1.02-1.35), and elevated triglycerides (OR 1.19, 95% CI 1.02-1.39). However, women who skipped dinner had reduced odds of having elevated fasting blood glucose levels (OR 0.74, 95% CI 0.58-0.94). CONCLUSIONS: Our findings suggest that meal frequency and the type of main meal skipped may be associated with MetS and emphasize the importance of consuming breakfast to prevent MetS.
Subject(s)
Metabolic Syndrome , Male , Humans , Adult , Female , Middle Aged , Metabolic Syndrome/epidemiology , Cross-Sectional Studies , Nutrition Surveys , Blood Glucose , Feeding Behavior , Meals , Republic of Korea/epidemiologyABSTRACT
Solute carrier family 35 member F3 (SLC35F3) mediates intracellular thiamine transport, which is crucial for carbohydrate metabolism as thiamine is required for key pathways such as glycolysis and the tricarboxylic acid cycle. This study aimed to investigate the impact of the interaction between SLC35F3 and dietary carbohydrate intake on the incidence of metabolic syndrome (MetS). The study included 3923 Korean adults over 40 years of age from the Korean Genome and Epidemiology Study. The association between dietary carbohydrate intake, SLC35F3 rs10910387 genotypes, and MetS incidence was studied using multivariable Cox proportional hazard models. Over an average of 8.5 years of follow-ups, we documented 1471 MetS cases. MetS incidence was 1.88 times greater in men with the TT genotype and the highest carbohydrate intake than in those with the CC genotype and lowest carbohydrate intake (Hazard Ratio (HR) 1.88, 95% confidence interval (CI) 1.03-3.41). MetS incidence were 2.22 and 2.53 times higher in women with the TT genotype and carbohydrate intake tertile 2 and 3, respectively, than those with the CC genotype and carbohydrate intake tertile 1 (HR 2.22, 95% CI 1.12-4.42; HR 2.53, 95% CI 1.38-4.61). In summary, we report a novel interaction between SLC35F3 rs10910387 genotypes and dietary carbohydrate intake on MetS in Koreans.
Subject(s)
Metabolic Syndrome , Male , Middle Aged , Humans , Adult , Female , Metabolic Syndrome/epidemiology , Metabolic Syndrome/genetics , Risk Factors , Diet , Incidence , Thiamine , Dietary Carbohydrates , Republic of Korea/epidemiologyABSTRACT
This study aimed to investigate the association between seaweed consumption and the odds of developing metabolic syndrome in middle-aged and elderly Koreans. The study included 5777 adults aged 40-69 years from 2001 to 2002 in the Ansan and Ansung cohorts of the Korean Genome and Epidemiology Study. Data on the consumption of seaweed, including laver and kelp/sea mustard, were obtained using a semiquantitative food frequency questionnaire. Multivariable logistic regression models were used to assess the association between seaweed consumption and the odds of developing metabolic syndrome and its components. Women in the highest tertile of laver consumption had lower odds of developing metabolic syndrome than those in the lowest tertile (adjusted odds ratio [AOR]: 0.70; 95% confidence interval [CI]: 0.54-0.92). Both men and women in the highest tertile of laver consumption had lower odds of abdominal obesity than those in the lowest tertile (AOR: 0.64, 95% CI: 0.42-0.98 for men; AOR: 0.53, 95% CI: 0.39-0.72 for women). These findings suggest that laver consumption is inversely associated with the odds of developing metabolic syndrome and abdominal obesity in Korean adults.
ABSTRACT
Cluster of differentiation 73 (CD73, also known as ecto-5'-nucleotidase) is an enzyme that converts AMP into adenosine. CD73 is a surface enzyme bound to the outside of the plasma membrane expressed in several cells and regulates immunity and inflammation. In particular, it is known to inhibit T cell-mediated immune responses. However, the regulation of CD73 expression by hormones in the uterus is not yet clearly known. In this study, we investigated the expression of CD73 in ovariectomized mice treated with estrogen or progesterone and its regulation in the mouse uterus during the estrous cycle. The level of CD73 expression was dynamically regulated in the uterus during the estrous cycle. CD73 protein expression was high in proestrus, estrus, and diestrus, whereas it was relatively low in the metestrus stage. Immunofluorescence revealed that CD73 was predominantly expressed in the cytoplasm of the luminal and glandular epithelium and the stroma of the endometrium. The expression of CD73 in ovariectomized mice was gradually increased by progesterone treatment. However, estrogen injection did not affect its expression. Moreover, CD73 expression was increased when estrogen and progesterone were co-administered and was inhibited by the pretreatment of the progesterone receptor antagonist RU486. These findings suggest that the expression of CD73 is dynamically regulated by estrogen and progesterone in the uterine environment, and that there may be a synergistic effect of estrogen and progesterone.
Subject(s)
5'-Nucleotidase/metabolism , Estrogens/pharmacology , Estrous Cycle/metabolism , Gene Expression Regulation/drug effects , Progesterone/pharmacology , Uterus/metabolism , 5'-Nucleotidase/genetics , Animals , Estrous Cycle/drug effects , Female , Mice , Mice, Inbred ICR , Progestins/pharmacology , Uterus/drug effectsABSTRACT
Tumor peptides associated with MHC class I molecules or their synthetic variants have attracted great attention for their potential use as vaccines to induce tumor-specific CTLs. However, the outcome of clinical trials of peptide-based tumor vaccines has been disappointing. There are various reasons for this lack of success, such as difficulties in delivering the peptides specifically to professional Ag-presenting cells, short peptide half-life in vivo, and limited peptide immunogenicity. We report here a novel peptide vaccination strategy that efficiently induces peptide-specific CTLs. Nanoparticles (NPs) were fabricated from a biodegradable polymer, poly(D,L-lactic-co-glycolic acid), attached to H-2Kb molecules, and then the natural peptide epitopes associated with the H-2Kb molecules were exchanged with a model tumor peptide, SIINFEKL (OVA257-268). These NPs were efficiently phagocytosed by immature dendritic cells (DCs), inducing DC maturation and activation. In addition, the DCs that phagocytosed SIINFEKL-pulsed NPs potently activated SIINFEKL-H-2Kb complex-specific CD8+ T cells via cross-presentation of SIINFEKL. In vivo studies showed that intravenous administration of SIINFEKL-pulsed NPs effectively generated SIINFEKL-specific CD8+ T cells in both normal and tumor-bearing mice. Furthermore, intravenous administration of SIINFEKL-pulsed NPs into EG7.OVA tumor-bearing mice almost completely inhibited the tumor growth. These results demonstrate that vaccination with polymeric NPs coated with tumor peptide-MHC-I complexes is a novel strategy for efficient induction of tumor-specific CTLs.
ABSTRACT
Cellular senescence of endothelial cells causes vascular dysfunction, promotes atherosclerosis, and contributes to the development of age-related vascular diseases. Sirtuin 6 (SIRT6), a conserved NAD+-dependent protein deacetylase, has beneficial effects against aging, despite the fact that its functional mechanisms are largely uncharacterized. Here, we show that SIRT6 protects endothelial cells from senescence. SIRT6 expression is progressively decreased during both oxidative stress-induced senescence and replicative senescence. SIRT6 deficiency leads to endothelial dysfunction, growth arrest, and premature senescence. Using genetically engineered endothelial cell-specific SIRT6 knockout mice, we also show that down-regulation of SIRT6 expression in endothelial cells exacerbates vascular aging. Expression microarray analysis demonstrated that SIRT6 modulates the expression of multiple genes involved in cell cycle regulation. Specifically, SIRT6 appears to regulate the expression of forkhead box M1 (FOXM1), a critical transcription factor for cell cycle progression and senescence. Overexpression of FOXM1 ameliorates SIRT6 deficiency-induced endothelial cell senescence. In this work, we demonstrate the role of SIRT6 as an anti-aging factor in the vasculature. These data may provide the basis for future novel therapeutic approaches against age-related vascular disorders.
Subject(s)
Aging/metabolism , Cellular Senescence , Endothelial Cells/metabolism , Forkhead Box Protein M1/metabolism , Sirtuins/metabolism , Animals , Down-Regulation , Male , Mice, Inbred C57BL , Mice, Knockout , Sirtuins/geneticsABSTRACT
Baculoviral inhibitor of apoptosis repeat-containing 5 (Birc5), also known as survivin, is a member of the inhibitor of apoptosis (IAP) family of proteins and regulates the size of tissues through cell division control. The uterus is the most dynamically sized organ among tissues during the estrous cycle. Although Birc5 is expressed in some terminally differentiated cells, the regulation of its expression in the uterus remains unknown. We investigated the regulation of Birc5 expression in the mouse uterus. RT-PCR analysis showed that Birc5 was expressed in various tissues, including the uterus; the expression level of Birc5 was significantly higher at the diestrus stage. Immunohistochemistry and Western blotting analysis revealed that Birc5 was more active in luminal and glandular epithelium than in endometrial stroma. In ovariectomized mice, Birc5 expression in the uterus was gradually increased by estrogen treatment; however, progesterone injection decreased its expression. Estrogen-induced Birc5 expression was blocked by treatment with estrogen receptor antagonist, ICI 182, 780 and progesterone-reduced Birc5 expression was inhibited by the progesterone receptor antagonist RU486. These results suggest that Birc5 expression is dynamically regulated by a combination of estrogen and progesterone via their receptor-mediated signaling.
Subject(s)
Epithelium/metabolism , Estrus/genetics , Survivin/genetics , Uterus/metabolism , Animals , Estrogens/metabolism , Estrus/metabolism , Female , Mice , Mice, Inbred ICR , Progesterone/metabolism , Survivin/metabolism , Uterus/cytology , Uterus/physiologyABSTRACT
The uterus is dynamically regulated in response to various signaling triggered by hormones during the estrous cycle. The Hippo signaling pathway is known as an important signaling for regulating cellular processes during development by balancing between cell growth and apoptosis. Serine/threonine protein kinase 3/4 (STK3/4) is a key component of the Hippo signaling network. However, the regulation of STK3/4-Hippo signaling in the uterus is little known. In this study, we investigated the regulation and expression of STK3/4 in the uterine endometrium during the estrous cycle. STK3/4 expression was dynamically regulated in the uterus during the estrous cycle. STK3/4 protein expression was gradually increased from the diestrus stage and reached the highest in the estrus stage. STK3/4 was exclusively localized in the luminal and glandular epithelial cells of the uterus, and phosphorylated STK3/4 was also increased at the estrus stage. Moreover, the increase of STK3/4 expression in uteri was induced by administration of estradiol, but not by progesterone injection in ovariectomized mice. Pretreatment with an estrogen receptor antagonist ICI 182,780 reduced estrogen-induced STK3/4 expression and its phosphorylation. The estrogen-induced STK3/4 expression was related to the increase in phosphorylation of downstream targets including LATS1/2 and YAP. These findings suggest that STK3/4-Hippo signaling acts a novel signaling pathway in the uterine epithelium and STK3/4-Hippo is one of key molecules for connecting between the estrogen downstream signaling pathway and the Hippo signaling pathway leading to regulate dynamic uterine epithelium during the estrous cycle.