HK1
Hexokinase-1 (EC 2.7.1.1) (Brain form hexokinase) (Hexokinase type I) (HK I) (Hexokinase-A)
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This experiment mainly optimized the extraction technology of Agaricus blazei polypeptide (ABp) and evaluated its protective effect on aging mice. In this study, a novel single component, the M is 3 kD, was isolated and purified from Agaricus blazei. An aging mouse model was established using D-galactose. After the administration of ABp, the contents of total antioxidant capacity (T-AOC), malondialdehyde (MDA), catalase (CAT), and reactive oxygen species were significantly changed. Through immunofluorescence staining, it was observed that ABp can reduce changes in brain tissue. The differential expression of genes was analyzed by RNA-seq. A total of 295 differentially expressed genes were screened out in the ABp group.RT-qPCR verified important genes and showed that the mRNA expression levels of Hsph1, Trim32, HK1, Hnrnpa1, and Grik5 were significantly increased, and those of ApoE, Atp1a3, Stxbp1, and Mapk8ip1 was significantly decreased. Western blotting showed that the protein expression levels of Keap1 and p53 were significantly lower, while the protein expression levels of Nrf2, HO-1, Hsph1, and Trim32 were significantly higher in the ABP group. ABp played an anti-aging role in an aging mouse model. The specific mechanism of action may be related to the regulation of the expression of the Keap1/Nrf2/P53 signaling pathway and related factors. PRACTICAL APPLICATIONS: The research may contribute to the development of ABp as functional foods or dietary supplements for anti-aging in the future.
Keywords
Keap1/Nrf2/ARE
- ABp (Agaricus Blazei polypeptide)
- RNA-seq
- aging
- oxidative stress
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia in the United States. Although the link between alcohol use and AD has been studied, preclinical research has potential to elucidate neurobiological mechanisms that underlie this interaction. This study was designed to test the hypothesis that nondependent alcohol drinking exacerbates the onset and magnitude of AD-like neural and behavioral pathology. We first evaluated the impact of voluntary 24-h, two-bottle choice home-cage alcohol drinking on the prefrontal cortex and amygdala neuroproteome in C57BL/6J mice and found a striking association between alcohol drinking and AD-like pathology. Bioinformatics identified the AD-associated proteins MAPT (Tau), amyloid beta precursor protein (APP), and presenilin-1 (PSEN-1) as the main modulators of alcohol-sensitive protein networks that included AD-related proteins that regulate energy metabolism (ATP5D, HK1, AK1, PGAM1, CKB), cytoskeletal development (BASP1, CAP1, DPYSL2 [CRMP2], ALDOA, TUBA1A, CFL2, ACTG1), cellular/oxidative stress (HSPA5, HSPA8, ENO1, ENO2), and DNA regulation (PURA, YWHAZ). To address the impact of alcohol drinking on AD, studies were conducted using 3xTg-AD mice that express human MAPT, APP, and PSEN-1 transgenes and develop AD-like brain and behavioral pathology. 3xTg-AD and wild-type mice consumed alcohol or saccharin for 4 months. Behavioral tests were administered during a 1-month alcohol-free period. Alcohol intake induced AD-like behavioral pathologies in 3xTg-AD mice including impaired spatial memory in the Morris Water Maze, diminished sensorimotor gating as measured by prepulse inhibition, and exacerbated conditioned fear. Multiplex immunoassay conducted on brain lysates showed that alcohol drinking upregulated primary markers of AD pathology in 3xTg-AD mice: Aβ 42/40 ratio in the lateral entorhinal and prefrontal cortex and total Tau expression in the lateral entorhinal cortex, medial prefrontal cortex, and amygdala at 1-month post alcohol exposure. Immunocytochemistry showed that alcohol use upregulated expression of pTau (Ser199/Ser202) in the hippocampus, which is consistent with late-stage AD. According to the NIA-AA Research Framework, these results suggest that alcohol use is associated with Alzheimer's pathology. Results also showed that alcohol use was associated with a general reduction in Akt/mTOR signaling via several phosphoproteins (IR, IRS1, IGF1R, PTEN, ERK, mTOR, p70S6K, RPS6) in multiple brain regions including hippocampus and entorhinal cortex. Dysregulation of Akt/mTOR phosphoproteins suggests alcohol may target this pathway in AD progression. These results suggest that nondependent alcohol drinking increases the onset and magnitude of AD-like neural and behavioral pathology in 3xTg-AD mice.
MeSH Terms
- Alcohol Drinking
- Alzheimer Disease
- Amyloid beta-Protein Precursor
- Animals
- Behavior, Animal
- Brain
- Disease Models, Animal
- Mice, Transgenic
- tau Proteins
Keywords
- Aging
- Amyloid beta
- Ethanol
- GSK
- Immunohistochemistry
- Morris Water Maze
- Prepulse inhibition
- Self-administration
- Tau pathology
- Transgenic mouse model
Glycated hemoglobin (HbA1c) is a stable index of chronic glycemic status and hyperglycemia associated with progressive development of insulin resistance and frank diabetes. It is also associated with premature aging and increased mortality. To uncover novel loci for HbA1c that are associated with healthy aging, we conducted a genome-wide association study (GWAS) using non-diabetic participants in the Long Life Family Study (LLFS), a study with familial clustering of exceptional longevity in the US and Denmark. A total of 4088 non-diabetic subjects from the LLFS were used for GWAS discoveries, and a total of 8231 non-diabetic subjects from the Atherosclerosis Risk in Communities Study (ARIC, in the MAGIC Consortium) and the Health, Aging, and Body Composition Study (HABC) were used for GWAS replications. HbA1c was adjusted for age, sex, centers, 20 principal components, without and with BMI. A linear mixed effects model was used for association testing. Two known loci at GCK rs730497 (or rs2908282) and HK1 rs17476364 were confirmed (p<5e-8). Of 25 suggestive (5e-8<p<1e-5) loci, one known (G6PC2 rs560887, replication p=5e-5) and one novel (OR10R3P/SPTA1- rs12041363, replication p=1e-17) loci were replicated (p<0.0019). Similar findings resulted when HbA1c was further adjusted for BMI. Further validations are crucial for the remaining suggestive loci including the emerged variant near OR10R3P/SPTA1. The analysis reconfirmed two known GWAS loci (GCK, HK1) and identified 25 suggestive loci including one reconfirmed variant in G6PC2 and one replicated variant near OR10R3P/SPTA1. Future focused survey of sequence elements containing mainly functional and regulatory variants may yield additional findings.
MeSH Terms
- Aged
- Cohort Studies
- Denmark
- Diabetes Mellitus
- Female
- Genome-Wide Association Study
- Genotype
- Glycated Hemoglobin A
- Humans
- Longevity
- Male
- Middle Aged
- Phenotype
- United States
Keywords
- Genome-wide association study
- Glucose
- Insulin resistance and diabetes
- Non-enzymatic glycation
- Premature aging processes