ABSTRACT
BACKGROUND: Substantial evidence has demonstrated that maternal high-fat (HF) consumption during gestation and lactation plays as a risk factor for neurodevelopmental alterations and subsequent neurological disorders. OBJECTIVE: We investigated the regulatory mechanisms of maternal fat consumption on brain development and function in offspring at different ages. METHODS: Mouse dams were fed either a control diet [low-fat (LF)] or an HF diet for 3 wk before mating and throughout pregnancy and lactation. Offspring were killed at postnatal day (PD) 21 (LF21 and HF21), and the rest were fed an HF diet for 12 wk until the killing at PD 105 (LF105 and HF105). The expression levels of genes and proteins in the brains of offspring were analyzed by microarray and immunoblotting, respectively. RESULTS: Maternal dietary fat content, offspring age, and their interaction affected the expression levels of 1215, 10,453, and 2105 genes, respectively. The 67 differentially expressed genes (DEGs) between the HF21 and LF21 groups were enriched in several Gene Ontology terms related to nervous system development. Among 45 DEGs of the HF105/LF105 comparison, several genes associated with neurotransmitter action are detected. In addition, we observed increased activation of the AMP-dependent protein kinase-cAMP response element binding protein signaling pathway in HF105/LF105 comparison. However, maternal fat content did not change the protein levels of amyloid-ß and tau hyperphosphorylation, the markers of neuropathogenesis. CONCLUSIONS: Maternal HF feeding altered the expression of genes involved in the development and neurotransmitter system in the brains of PD 21 and HF diet-fed PD 105 offspring, respectively. Especially, the absence of overlap between DEGs at each comparison highlights the dynamic nature of alterations in gene expression in offspring of dams fed an HF diet. Further investigation on older adult offspring is necessary to elucidate the effects of maternal fat intake on the brain pathophysiology of offspring.
Subject(s)
Brain , Diet, High-Fat , Maternal Nutritional Physiological Phenomena , Transcriptome , Animals , Female , Pregnancy , Brain/metabolism , Mice , Diet, High-Fat/adverse effects , Prenatal Exposure Delayed Effects , Male , Dietary Fats/administration & dosage , Obesity/genetics , Obesity/metabolism , Obesity/etiology , Mice, Inbred C57BL , LactationABSTRACT
Maternal consumption of low-protein (LP) diet during pregnancy has been demonstrated to increase the chances of adult offspring developing metabolic syndrome, and this risk can be exacerbated when the postnatal diets do not align with the prenatal conditions. However, in our previous study, focusing on serum parameters and gene expression patterns within adipose tissue, we discovered the presence of "healthy obesity" in young adult offspring from dams that were fed an LP, as a response to a postweaning high-fat (HF) diet. Here, we subsequently investigated the role played by the liver and skeletal muscle in alleviation of insulin resistance in male offspring that were fed either control (C/C group) or HF diet (C/HF and LP/HF groups) for 22 weeks. While a postweaning HF diet increased liver weight and hepatic triglyceride (TG) and cholesterol levels in offspring of control dams, these levels were lower in the LP/HF group compared to the C/HF group. Analysis of the liver transcriptome identified 430 differentially expressed genes (DEGs) in the LP/HF and C/HF comparison. Especially, downregulated DEGs were enriched in carbohydrate metabolism and the levels of DEGs were significantly correlated with the levels of markers for serum glucose homeostasis and hepatic lipid accumulation. In the LP/HF group compared to the C/HF group, there was a decrease in the gastrocnemius muscle weight, while no differences were observed in gene expression levels associated with muscle fiber phenotype, mitochondrial function, and inflammation. In conclusion, maternal LP diet induced changes in lipid and glucose metabolism within the liver, similar to what was observed in adipose tissue, while there were no alterations in metabolic functions in the skeletal muscle in young offspring mice fed an HF diet. Further research that investigating the enduring impact of nutritional transition on offspring is essential to gain a comprehensive grasp of developmental programming throughout their entire lifespan.
Subject(s)
Diet, High-Fat , Prenatal Exposure Delayed Effects , Pregnancy , Humans , Female , Mice , Animals , Male , Diet, High-Fat/adverse effects , Diet, Protein-Restricted/adverse effects , Maternal Nutritional Physiological Phenomena , Prenatal Exposure Delayed Effects/genetics , Prenatal Exposure Delayed Effects/metabolism , Liver/metabolism , Triglycerides/metabolism , Glucose/metabolism , Carbohydrate Metabolism , Gene Expression , Lipid Metabolism/geneticsABSTRACT
Purpose: This study aims to identify unmet needs and barriers for improving inpatient care for older adults at an academic hospital in Korea by using a qualitative focus group design and the Age-Friendly Health Systems (AFHS) framework. Patients and Methods: A total of 14 healthcare providers and employees participated in focus group interviews. Participants included medical doctors, registered nurses, a receptionist, a patient transporter, a pharmacist, a physical therapist, and a social worker. The data were analyzed qualitatively, as per the Consolidated Criteria for Reporting Qualitative Research guidelines. The analysis method encompassed a thematic framework analysis via the AFHS 4Ms framework, consisting of the four domains "What Matters", "Medication", "Mentation", and "Mobility". Results: Multiple barriers and unmet needs were identified using the AFHS 4Ms framework in the provision of inpatient care for older adults at the hospital. The main barriers identified in the "What matters" domain are a lack of shared decision-making and individualized care plans, as well as economic and safety-conscious preferences among some older patients. In the "Medications" domain, the main barriers to providing adequate and safe pharmacotherapy include patient and caregiver-related factors, increased complexity of medication use, and lack of institutional support systems. In the "Mentation" domain, the main issues identified are communication barriers related to patients, caregiver factors, and insufficient delirium management due to a lack of adequate processes/environments such as delirium identification. In the "Mobility" domain, the main challenges include reduced mobility and geriatric complications, unnecessary mobility restrictions, and the increased risk of falls due to lack of resources and environmental factors. Conclusion: The study highlighted the need for improvements in inpatient care for older adults at an academic hospital in Korea. Identified unmet needs and barriers can be used to guide a more patient-centered approaches for an age-friendly inpatient environment.
Subject(s)
Delirium , Health Personnel , Humans , Aged , Qualitative Research , Focus Groups , HospitalsABSTRACT
BACKGROUND: Dysphagia is a common problem with potentially serious consequences including malnutrition, dehydration, pneumonia, and death. However, there are challenges in screening for dysphagia in older adults. We assessed the feasibility of using the Clinical Frailty Scale (CFS) as a risk assessment tool for dysphagia. METHODS: This cross-sectional study was conducted at a tertiary teaching hospital from November 2021 to May 2022 and included 131 older patients (age ≥65 years) admitted to acute wards. We used the Eating Assessment Tool-10 (EAT-10), which is a simple measure for identifying individuals at risk of dysphagia, to assess the relationship between EAT-10 score and frailty status as measured using the CFS. RESULTS: The mean age of the participants was 74.3±6.7 years, and 44.3% were male. Twenty-nine (22.1%) participants had an EAT-10 score ≥3. The CFS was significantly associated with an EAT-10 score ≥3 after adjusting for age and sex (odds ratio=1.48; 95% confidence interval [CI], 1.09-2.02). The CFS was able to classify the presence of an EAT-10 score ≥3 (area under the receiver operating characteristic [ROC] curve=0.650; 95% CI, 0. 544-0.756). The cutoff point for predicting an EAT-10 score ≥3 was a CFS of 5 according to the highest Youden index, with a sensitivity of 82.8% and a specificity of 46.1%. The positive and negative predictive values were 30.4% and 90.4%, respectively. CONCLUSION: The CFS can be used as a tool to screen for the risk of swallowing difficulty in older inpatients to determine clinical management encompassing drug administration routes, nutritional support, prevention of dehydration, and further evaluation of dysphagia.
ABSTRACT
Apolipoprotein E knock out (ApoE-/-) mice, the widely used model for atherosclerosis, exhibits anti-obesity characteristics due to the impaired lipoprotein internalization. Since excessive accumulation of triglycerides and cholesterol in white adipose tissue (WAT) is shown to increase the risk of metabolic diseases, we investigated the effects of dietary high-fat high-cholesterol (HFHC) on gene expression profile and the possible role of cholesterol accumulation in WAT of ApoE-/- mice. Control (CON) and HFHC diets were provided to wild-type mice (WC, WH) and ApoE-/- mice (EC, EH) for 10 weeks. Although body and WAT weights were lower in the ApoE-/- group compared to the wild-type group, increases in cholesterol and lipid peroxides in WAT were only observed in the ApoE-/- group. Transcriptome analysis revealed 3660 and 839 differentially expressed genes (DEGs) in the EC/WC and EH/WH comparison, respectively. "Thermogenesis" and "Oxidative phosphorylation" KEGG pathways were found in the EC/WC comparison, but not in the EH/WH comparison. We identified 142 and 2585 DEGs in the WH/WC and EH/EC comparison respectively, indicating a stronger effect of HFHC on WAT of ApoE-/- mice. Gene ontology analysis of DEGs revealed the association of DEGs with "Regulation of inflammatory response" term, in the EH/EC comparison, but not in the WH/WC comparison. Especially, genes encoding scavenger receptors and toll-like receptors were associated with cholesterol and lipid peroxide levels in WAT of ApoE-/- mice, but not in wild-type mice. In conclusion, changes in gene expression profile of WAT were more pronounced in ApoE-/- mice compared to wild-type mice in response to HFHC, and these altered genes were related to inflammatory response. These data suggest that increased cholesterol accumulation in WAT by dietary HFHC may play a pivotal role in the regulation of gene expression in ApoE-/- mice.
ABSTRACT
BACKGROUND: Combined maternal and postnatal high-fat (HF) diet intake predisposes offspring to metabolic dysregulation during adulthood. As the inhibitory effects of leucine consumption on obesity and metabolic disorders have been reported, the effects of maternal leucine supplementation on metabolic dysregulation in adult offspring were investigated. METHODS: Female mice were exposed to a control (C) or HF diet, with or without leucine (L) supplementation (1.5%, w/v), 3 weeks before mating, during pregnancy, and during lactation (C, CL, HF, and HFL). Male offspring were exposed to an HF diet for 12 weeks after weaning (C/HF, CL/HF, HF/HF, and HFL/HF). Serum biochemical parameters were determined for both the dams and offspring. Oral glucose tolerance test and qRT-PCR analysis were used to investigate metabolic dysregulation in the offspring. RESULTS: HFL dams exhibited higher relative adipose tissue weights than HF dams. Body weight, relative adipose tissue weight, and serum glucose levels were lower in the HFL/HF offspring than in the HF/HF offspring. Maternal leucine supplementation tended to alleviate glucose intolerance in the offspring of HF diet-fed dams. Additionally, mRNA levels of fibroblast growth factor 21 (FGF21), a hepatokine associated with glucose homeostasis, were higher in HFL/HF offspring than in HF/HF offspring and were negatively correlated with adiposity and serum glucose levels. The mRNA levels of genes encoding a FGF21 receptor complex, Fgf receptor 1 and klotho ß, and its downstream targets, proliferator-activated receptor-γ co-activator 1α and sirtuin 1, were higher in adipose tissues of the HFL/HF offspring than in those of the HF/HF offspring. Serum lipid peroxide levels were lower in HFL dams than in HF dams and positively correlated with body and adipose tissue weights of offspring. CONCLUSIONS: Leucine supplementation in HF diet-fed dams, but not in control diet-fed dams, resulted in an anti-obesity phenotype accompanied by glucose homeostasis in male offspring challenged with postnatal HF feeding. Activation of FGF21 signaling in the adipose tissue of offspring may be responsible for these beneficial effects of leucine.
Subject(s)
Glucose Intolerance , Prenatal Exposure Delayed Effects , Pregnancy , Humans , Mice , Male , Female , Animals , Diet, High-Fat/adverse effects , Adiposity , Leucine/pharmacology , Leucine/metabolism , Maternal Nutritional Physiological Phenomena , Obesity/drug therapy , Obesity/etiology , Obesity/metabolism , Lactation/metabolism , Glucose/metabolism , RNA, Messenger/metabolism , Dietary Supplements , Body WeightABSTRACT
Patterns of whole-brain fMRI functional connectivity, or connectomes, are unique to individuals. Previous work has identified subsets of functional connections within these patterns whose strength predicts aspects of attention and cognition. However, overall features of these connectomes, such as how stable they are over time and how similar they are to a group-average (typical) or high-performance (optimal) connectivity pattern, may also reflect cognitive and attentional abilities. Here, we test whether individuals who express more stable, typical, optimal, and distinctive patterns of functional connectivity perform better on cognitive tasks using data from three independent samples. We find that individuals with more stable task-based functional connectivity patterns perform better on attention and working memory tasks, even when controlling for behavioral performance stability. Additionally, we find initial evidence that individuals with more typical and optimal patterns of functional connectivity also perform better on these tasks. These results demonstrate that functional connectome stability within individuals and similarity across individuals predicts individual differences in cognition.
Subject(s)
Connectome , Humans , Connectome/methods , Brain/diagnostic imaging , Cognition , Memory, Short-Term , Attention , Magnetic Resonance Imaging/methods , Nerve NetABSTRACT
Soy protein, containing isoflavones and bioactive peptides, is shown to have anti-obesity effects, but the main contributor and underlying mechanisms remain unclear. Recent studies have demonstrated that circulating microRNAs (miRNAs) act as important mediators in obesity and metabolic processes. In this study, we investigated whether soy protein components have distinctive effects on adiposity and circulating miRNA profiles in obese mice. C57BL/6J mice were divided into 4 groups, and each group was fed with a control, high-fat (HF), HF with low-isoflavone soy protein (HF/S), or HF with high-isoflavone soy protein (HF/SI) diet for 16 weeks. In the HF/SI group, changes in the serum adipokine levels, adipocyte diameter, and the number of crown-like structures (CLS) were alleviated compared to those of the HF group. In the HF/S group, the number of CLS was reduced. Decreases in body and adipose tissue weights were not observed in both HF/S and HF/SI groups. Through microarray analysis of serum miRNAs, we identified 23 differentially expressed miRNAs (DEMs) among the groups. The levels of most circulating DEMs were correlated with body weight, serum biochemical parameters, and adipose tissue histology. Functional analysis of predicted target genes of DEMs from both HF vs. CON and HF/S vs. CON comparisons revealed several cancer-related pathways. Only 2 DEMs were identified in the HF/SI vs. CON comparison. In conclusion, the present study confirmed that soy isoflavones are the main contributor to the health-beneficial effects of soy protein in diet-induced obesity. Notably, the extent of serum miRNA dysregulation coincided with obesity and altered the circulating adipokine levels. These findings provide additional insights into the role of soy protein in the regulation of circulating miRNAs in diet-induced obesity. Further work is required to validate the proposed functions of miRNAs in target tissues.
Subject(s)
Isoflavones , MicroRNAs , Mice , Animals , Diet, High-Fat/adverse effects , Adipokines , Soybean Proteins , Mice, Inbred C57BL , Obesity/drug therapy , Obesity/genetics , Obesity/metabolism , Mice, Obese , Isoflavones/pharmacology , MicroRNAs/geneticsABSTRACT
AIMS: It is well known that a low-status of B vitamins is associated with cognitive impairment. However, the impact of vitamin B6 (VB6) restriction on neurodegenerative diseases and its underlying mechanisms are rarely understood. This study investigated whether VB6 restriction aggravates neurodegeneration in mice fed either a low-fat (LF) control diet or a high-fat (HF) diet. MAIN METHODS: Six-week-old male C57BL/6J mice were divided into 4 groups (LF7, LF1, HF7 and HF1) and fed either an LF diet [7 mg pyridoxine (PN)/kg diet], an LF with 1 mg PN/kg diet, an HF diet or an HF with 1 mg PN/kg diet for 16 weeks. Brain cortex and hippocampus were collected and used for the determination of biochemical parameters including VB6, lipid peroxides, and neurodegeneration-related mRNA and protein levels. KEY FINDINGS: VB6 restriction reduced levels of the biologically active form of VB6, pyridoxal phosphate (PLP) in the brain. Low consumption of VB6 inactivated brain-derived neurotrophic factor signaling and cell proliferation, and induced oxidative stress, endoplasmic reticulum stress and apoptotic cell death. Significant correlation between brain lipid peroxide levels and PLP levels were observed. VB6 restriction also induced characteristic features of neurodegeneration such as amyloid-ß deposition and tau hyperphosphorylation. Similarly, high-fat diet increased parameters associated with neurodegeneration. Aggravating effects of VB6 restriction were observed in both LF control and HF groups. SIGNIFICANCE: Dietary VB6 restriction plays a key role in neurodegeneration, and VB6 restriction worsens HF-induced neuronal damage in mice. Our study emphasizes the essential role of VB6 in maintaining brain health.
Subject(s)
Vitamin B 6 , Vitamin B Complex , Male , Mice , Animals , Pyridoxine , Diet, High-Fat/adverse effects , Pyridoxal Phosphate , Brain-Derived Neurotrophic Factor , Lipid Peroxides , Mice, Inbred C57BL , RNA, MessengerABSTRACT
Background: While the Clinical Frailty Scale (CFS) has been extensively validated for predicting health outcomes in older adults, the role of the at-point CFS at the time of examination is unclear. We aimed to examine the ability of the at-point CFS for predicting clinical outcomes of older inpatients. Methods: As a single-center and prospective cohort study, we enrolled 1,016 older adults who were 65 years or older and were admitted to one of 9 medical or surgical units from May 2021 to September 2021. The associations of the at-point CFS with outcomes of falls, delirium, pressure ulcers, 30-day unplanned readmission and/or emergency department (ED) visits, institutionalization, and a composite outcome were analyzed. Results: In the study population (n = 1,016), 26 patients had incident pressure ulcers, 6 patients had falls, 50 patients experienced delirium, and 13 patients died during hospitalization. Also, 37 patients experienced an ED visit and 22 patients had an unplanned readmission within 30 days after discharge. The composite outcome was 1.7% among patients with the CFS < 5 and 28.5% among patients with the CFS ≥ 5. The higher CFS was associated with an increased risk of a fall [odds ratio (OR) 1.74 (1.01-3.01)], pressure ulcers [OR 3.02 (2.15-4.23)], delirium [OR 2.72 (2.13-3.46)], 30-day readmission [OR 1.94 (1.44-2.62)], ED visit [OR 1.81 (1.47-2.23)], death [OR 3.27 (2.02-5.29)], and institutionalization after discharge [OR 1.88 (1.62-2.18)]. Conclusion: The at-point CFS assessed in older inpatients can screen high-risk individuals who might experience adverse geriatric conditions and in-hospital outcomes.
ABSTRACT
The human brain flexibly controls different cognitive behaviors, such as memory and attention, to satisfy contextual demands. Much progress has been made to reveal task-induced modulations in the whole-brain functional connectome, but we still lack a way to model context-dependent changes. Here, we present a novel connectome-to-connectome (C2C) transformation framework that enables us to model the brain's functional reorganization from one connectome state to another in response to specific task goals. Using functional magnetic resonance imaging data from the Human Connectome Project, we demonstrate that the C2C model accurately generates an individual's task-related connectomes from their task-free (resting-state) connectome with a high degree of specificity across seven different cognitive states. Moreover, the C2C model amplifies behaviorally relevant individual differences in the task-free connectome, thereby improving behavioral predictions with increased power, achieving similar performance with just a third of the subjects needed when relying on resting-state data alone. Finally, the C2C model reveals how the brain reorganizes between cognitive states. Our observations support the existence of reliable state-specific subsystems in the brain and demonstrate that we can quantitatively model how the connectome reconfigures to different cognitive states, enabling more accurate predictions of behavior with fewer subjects.
Subject(s)
Connectome , Attention , Brain/physiology , Cognition/physiology , Connectome/methods , Humans , Magnetic Resonance Imaging/methods , Nerve Net/diagnostic imaging , Nerve Net/physiologyABSTRACT
Attention is central to many aspects of cognition, but there is no singular neural measure of a person's overall attentional functioning across tasks. Here, using original data from 92 participants performing three different attention-demanding tasks during functional magnetic resonance imaging, we constructed a suite of whole-brain models that can predict a profile of multiple attentional components (sustained attention, divided attention and tracking, and working memory capacity) for novel individuals. Multiple brain regions across the salience, subcortical and frontoparietal networks drove accurate predictions, supporting a common (general) attention factor across tasks, distinguished from task-specific ones. Furthermore, connectome-to-connectome transformation modelling generated an individual's task-related connectomes from rest functional magnetic resonance imaging, substantially improving predictive power. Finally, combining the connectome transformation and general attention factor, we built a standardized measure that shows superior generalization across four independent datasets (total N = 495) of various attentional measures, suggesting broad utility for research and clinical applications.
Subject(s)
Connectome , Attention , Brain/diagnostic imaging , Connectome/methods , Humans , Magnetic Resonance Imaging/methods , Memory, Short-TermABSTRACT
A considerable number of studies have reported that maternal protein restriction may disturb fetal growth and organ development due to a lower availability of amino acids. Leucine, one of branched-chain amino acid (BCAA) promotes protein synthesis through mechanistic target of rapamycin signaling. Here, we investigated the effects of BCAA supplementation in the dams fed a low-protein diet on serum and hepatic biochemical parameters of protein metabolism of dams and their offspring. Female ICR mice were fed a control (20% casein), a low-protein (10% casein), a low-protein with 2% BCAAs or a low-protein with 2% alanine diet for 2 weeks before mating and then throughout pregnancy and lactation. Alanine was used as an amino nitrogen control for the BCAA. Dams and their male offspring were sacrificed at postnatal day 21. There were no changes in body weight and fat mass in low-protein fed dams; however, BCAA supplementation significantly increased fat mass and serum leptin levels. Low-protein diet consumption reduced maternal protein synthesis based on biochemical analysis of serum albumin and hepatic protein levels and immunoblotting of S6 protein, which were increased by BCAA and alanine supplementation. Offspring from dams fed a low-protein diet exhibited lower body and organ weights. Body weight and hepatic protein levels of the offspring were increased by alanine supplementation. However, the decreased serum biochemical parameters, including glucose, triglyceride, total protein and albumin levels in the low-protein offspring group were not changed in response to BCAA or alanine supplementation. A reduced density of the hepatic vessel system in the offspring from dams fed a low-protein diet was restored in the offspring from dams fed either BCAA and alanine-supplemented diet. These results suggest that supplementation of amino nitrogen per se may be responsible for inducing hepatic protein synthesis in the dams fed a low-protein diet and alleviating the distorted growth and liver development of their offspring.
Subject(s)
Caseins , Diet, Protein-Restricted , Alanine/metabolism , Alanine/pharmacology , Amino Acids, Branched-Chain/metabolism , Animals , Biomarkers/metabolism , Body Weight , Caseins/pharmacology , Diet, High-Fat , Dietary Supplements , Female , Liver/metabolism , Male , Mice , Mice, Inbred ICR , PregnancyABSTRACT
Studies have shown that the higher prevalence of colorectal cancers among patients with inflammatory bowel disease. Thus, proinflammatory stimulus due to a high-fat diet may impose a higher risk on the development of colorectal cancer. In the present study, we applied a transcriptomic approach to characterize the molecular mechanism(s) by which high-fat feeding aggravates colitis-associated colorectal cancer (CAC). A high-fat diet was supplied in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model for 10 weeks and then the severity of CAC and global gene expression in colon were assessed. Although consumption of high-fat diet did not significantly aggravate CAC, it substantially changed gene expression profile in colon. In AOM/DSS treated mice (AD group) and AD mice fed a high-fat diet (AD + HF group), 34 and 54 DEGs were enriched in 'pathways in cancer', respectively. Notably, high-fat diet upregulated the expression of genes associated with spliceosome and ribosome biogenesis, and downregulated the expression of genes associated with lipid catabolism in mice treated with AOM/DSS. In addition, we identified that DEGs between the AD and AD + HF groups, were enriched in 'metabolic pathways', especially amino acid and nucleotide metabolism. Taken together, this study provides the molecular mechanism in understanding the high-fat diet-mediated CAC development.
Subject(s)
Colitis-Associated Neoplasms/genetics , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Diet, High-Fat , Gene Expression Regulation, Neoplastic , Animals , Azoxymethane , Colitis-Associated Neoplasms/pathology , Dextran Sulfate , Gene Expression Profiling , Male , Mice, Inbred C57BLABSTRACT
Although a dietary phytochemical luteolin has been shown to regulate various anticancer mechanisms, a role of luteolin in autophagy regulation is mostly unidentified. Here, we investigated whether luteolin exhibits its anticancer effects by induction of apoptosis and autophagy in a p53-dependent manner in colon cancer cells. Cell viability was determined using trypan blue exclusion test. The expressions of proteins and mRNAs were measured by immunoblotting and reverse transcription polymerase chain reaction, respectively. Luteolin at 10 - 20 µM induced cytotoxicity in p53 wild-type HCT116 colon cancer cells but not in p53 mutant HT-29 cells and normal colon cells. Luteolin exhibited its anticancer effect by increasing p53 phosphorylation and p53 target gene expression, leading to apoptosis and cell cycle arrest in HCT116 cells. We identified that luteolin can induce autophagy in p53 wild-type cells but not in p53 mutant cells, suggesting that luteolin-induced autophagy is p53-dependent; however, chloroquine-mediated inhibition of autophagy did not alter cytotoxicity and apoptosis of cells treated with luteolin. In conclusion, the present data showed that luteolin inhibits the growth of HCT116 colon cancer cells through p53-dependent regulation of apoptosis and cell cycle arrest regardless of the induction of autophagy.
Subject(s)
Colonic Neoplasms , Luteolin , Apoptosis , Autophagy , Colonic Neoplasms/drug therapy , Colonic Neoplasms/metabolism , HCT116 Cells , Humans , Luteolin/pharmacology , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of hepatocellular carcinoma (HCC). Although the intracellular cholesterol accumulation has been demonstrated to regulate the gene expression responsible for steatohepatitis, the role played by cholesterol in the development of NAFLD-associated HCC has not been fully elucidated. In this study, using microarray analysis, we investigated the molecular mechanisms governing cholesterol-mediated progression of NAFLD. To ensure hepatic cholesterol accumulation, either a high-fat and high-cholesterol (HFHC) diet or a high-fat and high-cholesterol with cholic acid (HFHCCA) diet was fed to diethylnitrosamine (DEN)-injected C57BL/6J mice for 10 weeks. While an HFHC diet increased hepatic triglyceride levels, an HFHCCA diet induced hepatic cholesterol accumulation by reducing bile acid biosynthesis in DEN-injected mice. Livers from both HFHC and HFHCCA groups exhibited increases in steatosis and necrosis; however, histological features of HCC were not observed in any of the experimental groups. Hepatic gene expression profile of the HFHCCA group was different from those of other groups. Functional analysis showed that cholic acid supplementation upregulated differentially expressed genes (DEGs) associated with inflammation, proliferation, apoptosis, chemical drug response, and cancer signaling pathway. Downregulated DEGs were associated with steroid metabolism, mitochondrial function, and oxidative phosphorylation pathway. Furthermore, hepatic cholesterol accumulation lowered the expression of DEGs associated with energy and macronutrient metabolism, especially amino acid metabolism. In this study, the results of a global gene expression profile demonstrated that feeding the HFHCCA diet to DEN-injected mice accelerated the carcinogenic progression of NAFLD, implicating the critical role played by hepatic accumulation of cholesterol.
Subject(s)
Carcinogenesis , Cholesterol, Dietary , Cholesterol/metabolism , Cholic Acid/administration & dosage , Diet, High-Fat , Liver/metabolism , Non-alcoholic Fatty Liver Disease/physiopathology , Amino Acids/metabolism , Animals , Carcinoma, Hepatocellular/physiopathology , Dietary Supplements , Diethylnitrosamine/pharmacology , Disease Progression , Gene Expression Regulation , Lipid Metabolism , Liver/pathology , Male , Metabolic Networks and Pathways , Mice , Mice, Inbred C57BL , Mitochondria, Liver/metabolism , Non-alcoholic Fatty Liver Disease/pathology , TranscriptomeABSTRACT
While there is a substantial amount of work studying multilingualism's effect on cognitive functions, little is known about how the multilingual experience modulates the brain as a whole. In this study, we analyzed data of over 1,000 children from the Adolescent Brain Cognitive Development (ABCD) Study to examine whether monolinguals and multilinguals differ in executive function, functional brain connectivity, and brain-behavior associations. We observed significantly better performance from multilingual children than monolinguals in working-memory tasks. In one finding, we were able to classify multilinguals from monolinguals using only their whole-brain functional connectome at rest and during an emotional n-back task. Compared to monolinguals, the multilingual group had different functional connectivity mainly in the occipital lobe and subcortical areas during the emotional n-back task and in the occipital lobe and prefrontal cortex at rest. In contrast, we did not find any differences in behavioral performance and functional connectivity when performing a stop-signal task. As a second finding, we investigated the degree to which behavior is reflected in the brain by implementing a connectome-based behavior prediction approach. The multilingual group showed a significant correlation between observed and connectome-predicted individual working-memory performance scores, while the monolingual group did not show any correlations. Overall, our observations suggest that multilingualism enhances executive function and reliably modulates the corresponding brain functional connectome, distinguishing multilinguals from monolinguals even at the developmental stage.
Subject(s)
Connectome/methods , Executive Function/physiology , Multilingualism , Adolescent , Brain/physiology , Brain Mapping/methods , Child , Cognition/physiology , Female , Forecasting/methods , Humans , Magnetic Resonance Imaging , Male , Memory, Short-Term , Prefrontal CortexABSTRACT
Although vitamin B6 is contained in various foods, its deficiency is one of the most common micronutrient deficiencies worldwide. Furthermore, patients with obesity and cardiovascular disease are more likely to have suboptimal vitamin B6 status than healthy people. Therefore, we investigated the effects of dietary vitamin B6 restriction on hepatic gene expression and function in obese mice. C57BL/6J male mice were fed a low-fat (LF) or high-fat (HF) diet in combination with sufficient (7 mg pyridoxine/kg diet) or insufficient (1 mg) amounts of vitamin B6 for 16 weeks. Analysis of microarray data revealed that expressions of 4000 genes were significantly altered by the experimental diets (LF7, LF1, HF7, and HF1). The effects of dietary fat content on gene expressions were markedly greater than vitamin B6 content. Only three differentially expressed genes (DEGs) were overlapped between the LF1/LF7 and HF1/HF7 comparison. In the LF1/LF7 comparison, 54 upregulated DEGs were enriched in gene ontology (GO) terms associated with the sterol metabolic process and 54 downregulated DEGs were enriched in GO terms associated with immune response. In HF1/HF7 comparison, 26 upregulated DEGs were enriched in GO terms associated with amino acid catabolic process. High-fat consumption downregulated gene expressions associated with vitamin B6-dependent pathways. In conclusion, our data suggest that obesity may differentially regulate vitamin B6-associated metabolic pathways in the body.
Subject(s)
Obesity/metabolism , Signal Transduction/drug effects , Transcriptome/drug effects , Vitamin B 6 Deficiency/metabolism , Vitamin B 6/pharmacology , Animals , Diet, Fat-Restricted , Diet, High-Fat , Dietary Fats/metabolism , Down-Regulation/drug effects , Gene Ontology , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Obesity/complications , Up-Regulation/drug effects , Vitamin B 6 Deficiency/complicationsABSTRACT
Maternal protein restriction is associated with increased risk of insulin resistance and inflammation in adulthood offspring. Here, we investigated whether maternal protein restriction could alter the risk of metabolic syndrome in postweaning high-fat (HF)-diet-challenged offspring, with focus on epididymal adipose tissue gene expression profile. Female ICR mice were fed a control (C) or a low-protein (LP) diet for two weeks before mating and throughout gestation and lactation, and their male offspring were fed an HF diet for 22 weeks (C/HF and LP/HF groups). A subset of offspring of control dams was fed a low-fat control diet (C/C group). In response to postweaning HF diet, serum insulin level and the homeostasis model assessment of insulin resistance (HOMA-IR) were increased in control offspring. Maternal LP diet decreased HOMA-IR and adipose tissue inflammation, and increased serum adiponectin level in the HF-diet-challenged offspring. Accordingly, functional analysis revealed that differentially expressed genes (DEGs) enriched in cytokine production were downregulated in the LP/HF group compared to the C/HF group. We also observed the several annotated gene ontology terms associated with innate immunity and phagocytosis in down-regulated DEGs between LP/HF and C/C groups. In conclusion, maternal protein restriction alleviated insulin resistance and inflammation in young offspring mice fed a HF diet but may impair development of immune system in offspring.
Subject(s)
Adipose Tissue/metabolism , Animal Nutritional Physiological Phenomena/physiology , Diet, High-Fat/adverse effects , Diet, Protein-Restricted , Gene Expression Regulation , Gene Expression , Inflammation/genetics , Insulin Resistance , Maternal-Fetal Exchange/physiology , Animals , Cytokines/genetics , Cytokines/metabolism , Down-Regulation , Female , Immunity, Innate/genetics , Male , Mice, Inbred ICR , Phagocytosis/genetics , PregnancyABSTRACT
The ability to sustain attention differs across people and changes within a single person over time. Although recent work has demonstrated that patterns of functional brain connectivity predict individual differences in sustained attention, whether these same patterns capture fluctuations in attention within individuals remains unclear. Here, across five independent studies, we demonstrate that the sustained attention connectome-based predictive model (CPM), a validated model of sustained attention function, generalizes to predict attentional state from data collected across minutes, days, weeks, and months. Furthermore, the sustained attention CPM is sensitive to within-subject state changes induced by propofol as well as sevoflurane, such that individuals show functional connectivity signatures of stronger attentional states when awake than when under deep sedation and light anesthesia. Together, these results demonstrate that fluctuations in attentional state reflect variability in the same functional connectivity patterns that predict individual differences in sustained attention.