The potential diagnostic accuracy of urine formaldehyde levels in Alzheimer’s disease: A systematic review and meta-analysis

BackgroundFormaldehyde (FA), a toxic aldehyde, has been shown to be associated with a variety of cognitive disorders, including Alzheimer’s disease (AD). There is increasing evidence that FA levels are significantly increased in AD patients and may be involved in the pathological process of AD. The aim of this study was to assess the potential diagnostic value of urine FA levels in AD using meta-analysis techniques.MethodsOriginal reports of morning urine FA levels in AD patients and healthy controls (HCs) were included in the meta-analysis. Standardized mean differences (SMD) were calculated using a random-effects model, heterogeneity was explored using methodological, age, sex difference and sensitivity analyses, and receiver operating characteristic (ROC) curves were constructed to assess the diagnostic value of urine FA levels in AD.ResultsA total of 12 studies were included, and the urine FA levels of 874 AD patients and 577 HCs were reviewed. Compared with those in HCs, the FA levels were significantly increased in AD patients. The heterogeneity of the results did not affect their robustness, and results of the area under the curve (AUC) suggested that urine FA levels had good potential diagnostic value.ConclusionUrine FA levels are involved in AD disease progression and are likely to be useful as a potential biomarker for clinical auxiliary diagnosis. However, further studies are needed to validate the results of this study

Ribosylation Rapidly Induces α-Synuclein to Form Highly Cytotoxic Molten Globules of Advanced Glycation End Products

BACKGROUND: Alpha synuclein (alpha-Syn) is the main component of Lewy bodies which are associated with several neurodegenerative diseases such as Parkinson's disease. While the glycation with D-glucose that results in alpha-Syn misfold and aggregation has been studied, the effects of glycation with D-ribose on alpha-Syn have not been investigated. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that ribosylation induces alpha-Syn misfolding and generates advanced glycation end products (AGEs) which form protein molten globules with high cytotoxcity. Results from native- and SDS-PAGE showed that D-ribose reacted rapidly with alpha-Syn, leading to dimerization and polymerization. Trypsin digestion and sequencing analysis revealed that during ribosylation the lysinyl residues (K(58), K(60), K(80), K(96), K(97) and K(102)) in the C-terminal region reacted more quickly with D-ribose than those of the N-terminal region. Using Western blotting, AGEs resulting from the glycation of alpha-Syn were observed within 24 h in the presence of D-ribose, but were not observed in the presence of D-glucose. Changes in fluorescence at 410 nm demonstrated again that AGEs were formed during early ribosylation. Changes in the secondary structure of ribosylated alpha-Syn were not clearly detected by CD spectrometry in studies on protein conformation. However, intrinsic fluorescence at 310 nm decreased markedly in the presence of D-ribose. Observations with atomic force microscopy showed that the surface morphology of glycated alpha-Syn looked like globular aggregates. thioflavin T (ThT) fluorescence increased during alpha-Syn incubation regardless of ribosylation. As incubation time increased, ribosylation of alpha-Syn resulted in a blue-shift (approximately 100 nm) in the fluorescence of ANS. The light scattering intensity of ribosylated alpha-Syn was not markedly different from native alpha-Syn, suggesting that ribosylated alpha-Syn is present as molten protein globules. Ribosylated products had a high cytotoxicity to SH-SY5Y cells, leading to LDH release and increase in the levels of reactive oxygen species (ROS). CONCLUSIONS/SIGNIFICANCE: alpha-Syn is rapidly glycated in the presence of D-ribose generating molten globule-like aggregations which cause cell oxidative stress and result in high cytotoxicity

Malondialdehyde Suppresses Cerebral Function by Breaking Homeostasis between Excitation and Inhibition in Turtle Trachemys scripta

The levels of malondialdehyde (MDA) are high in the brain during carbonyl stress, such as following daily activities and sleep deprivation. To examine our hypothesis that MDA is one of the major substances in the brain leading to fatigue, the influences of MDA on brain functions and neuronal encodings in red-eared turtle (Trachemys scripta) were studied. The intrathecal injections of MDA brought about sleep-like EEG and fatigue-like behaviors in a dose-dependent manner. These changes were found associated with the deterioration of encoding action potentials in cortical neurons. In addition, MDA increased the ratio of γ-aminobutyric acid to glutamate in turtle's brain, as well as the sensitivity of GABAergic neurons to inputs compared to excitatory neurons. Therefore, MDA, as a metabolic product in the brain, may weaken cerebral function during carbonyl stress through breaking the homeostasis between excitatory and inhibitory neurons

The genetic correlation and causal association between key factors that influence vascular calcification and cardiovascular disease incidence

Background: Serum calcium (Ca), vitamin D (VD), and vitamin K (VK) levels are key determinants of vascular calcification, which itself impacts cardiovascular disease (CVD) risk. The specific relationships between the levels of these different compounds and particular forms of CVD, however, remain to be fully defined. Objective: This study was designed to explore the associations between these serum levels and CVDs with the goal of identifying natural interventions capable of controlling vascular calcification and thereby protecting against CVD pathogenesis, extending the healthy lifespan of at-risk individuals.Methods: Linkage disequilibrium score (LDSC) regression and a two-sample Mendelian randomization (MR) framework were leveraged to systematically examine the causal interplay between these serum levels and nine forms of CVD, as well as longevity through the use of large publically accessible Genome-Wide Association Studies (GWAS) datasets. The optimal concentrations of serum Ca and VD to lower CVD risk were examined through a restrictive cubic spline (RCS) approach.Results: After Bonferroni correction, the positive genetic correlations were observed between serum Ca levels and myocardial infarction (MI) (p = 1.356E–04), as well as coronary artery disease (CAD) (p = 3.601E–04). Negative genetic correlations were detected between levels of VD and CAD (p = 0.035), while elevated VK1 concentrations were causally associated with heart failure (HF) [odds ratios (OR) per 1-standard deviation (SD) increase: 1.044], large artery stroke (LAS) (OR per 1-SD increase: 1.172), and all stroke (AS) (OR per 1-SD increase: 1.041). Higher serum Ca concentrations (OR per 1-SD increase: 0.865) and VD levels (OR per 1-SD increase: 0.777) were causally associated with reduced odds of longevity. These findings remained consistent in sensitivity analyses, and serum Ca and VD concentrations of 2.376 mmol/L and 46.8 nmol/L, respectively, were associated with a lower CVD risk (p &lt; 0.001). Conclusion: Our findings support a genetic correlation between serum Ca and VD and CVD risk, and a causal relationship between VK1 levels and CVD risk. The optimal serum Ca (2.376 mmol/L) and VD levels (46.8 nmol/L) can reduce cardiovascular risk.</p

DSSylation, a novel protein modification targets proteins induced by oxidative stress, and facilitates their degradation in cells

Timely removal of oxidatively damaged proteins is critical for cells exposed to oxidative stresses; however, cellular mechanism for clearing oxidized proteins is not clear. Our study reveals a novel type of protein modification that may play a role in targeting oxidized proteins and remove them. In this process, DSS1 (deleted in split hand/split foot 1), an evolutionally conserved small protein, is conjugated to proteins induced by oxidative stresses in vitro and in vivo, implying oxidized proteins are DSS1 clients. A subsequent ubiquitination targeting DSS1-protein adducts has been observed, suggesting the client proteins are degraded through the ubiquitin-proteasome pathway. The DSS1 attachment to its clients is evidenced to be an enzymatic process modulated by an unidentified ATPase. We name this novel protein modification as DSSylation, in which DSS1 plays as a modifier, whose attachment may render target proteins a signature leading to their subsequent ubiquitination, thereby recruits proteasome to degrade them.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-013-0018-8) contains supplementary material, which is available to authorized users

D-Ribose Induces Cellular Protein Glycation and Impairs Mouse Spatial Cognition

BACKGROUND: D-ribose, an important reducing monosaccharide, is highly active in the glycation of proteins, and results in the rapid production of advanced glycation end products (AGEs) in vitro. However, whether D-ribose participates in glycation and leads to production of AGEs in vivo still requires investigation. METHODOLOGY/PRINCIPAL FINDINGS: Here we treated cultured cells and mice with D-ribose and D-glucose to compare ribosylation and glucosylation for production of AGEs. Treatment with D-ribose decreased cell viability and induced more AGE accumulation in cells. C57BL/6J mice intraperitoneally injected with D-ribose for 30 days showed high blood levels of glycated proteins and AGEs. Administration of high doses D-ribose also accelerated AGE formation in the mouse brain and induced impairment of spatial learning and memory ability according to the performance in Morris water maze test. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that D-ribose but not D-glucose reacts rapidly with proteins and produces significant amounts of AGEs in both cultured cells and the mouse brain, leading to accumulation of AGEs which may impair mouse spatial cognition

Fasting induces a high level of 3-nitrotyrosine in the brain of rats

Although the relationship between hyperglycemia (using diabetic animal model) and plasma nitrotyrosine level has been studied, the effect of hypoglycemia on nitrotyrosine level in the brain has not been addressed. Here, we evaluated nitration of protein, the colocalization of nitration with alpha-synuclein, activity of inducible nitric oxide synthase, and nitric oxide content using fasting and diabetic animal models. The results showed that signals of alpha-synuclein were widely distributed in most parts of the pallium, midbrain, hippocampus and cerebellum, as indicated by immunohistochemistry. Most signals of the 3-nitrotyrosine were colocalized with those of alpha-synuclein in the midbrain of fasting rats. The level of proteins containing 3-nitrotyrosine was significantly increased in the brain of fasting rats in Western blotting, especially in the midbrain, compared with control rats. In addition, the 3-nitrotyrosine signals increased in hippocampus of diabetic rats. Immunoprecipitation showed that alpha-synuclein was nitrated in the fasting rats. The iNOS activity and nitric oxide levels were significantly increased in both fasting and diabetic animals. The enhanced 3-nitrotyrosine level in the brain of fasting rats suggests that nitration of protein including alpha-synuclein in the midbrain is more affected by hypoglycemia in fasting than hyperglycemia in diabetic rats. (C) 2010 Elsevier Ireland Ltd. All rights reserved

Brain Formaldehyde is Related to Water Intake Behavior

A promising strategy for the prevention of Alzheimer&#39;s disease (AD) is the identification of agerelated changes that place the brain at risk for the disease. Additionally, AD is associated with chronic dehydration, and one of the significant changes that are known to result in metabolic dysfunction is an increase in the endogenous formaldehyde (FA) level. Here, we demonstrate that the levels of uric formaldehyde in AD patients were markedly increased compared with normal controls. The brain formaldehyde levels of wild-type C57 BL/6 mice increased with age, and these increases were followed by decreases in their drinking frequency and water intake. The serum arginine vasopressin (AVP) concentrations were also maintained at a high level in the 10-month-old mice. An intravenous injection of AVP into the tail induced decreases in the drinking frequency and water intake in the mice, and these decreases were associated with increases in brain formaldehyde levels. An ELISA assay revealed that the AVP injection increased both the protein level and the enzymatic activity of semicarbazide-sensitive amine oxidase (SSAO), which is an enzyme that produces formaldehyde. In contrast, the intraperitoneal injection of formaldehyde increased the serum AVP level by increasing the angiotensin II (ANG II) level, and this change was associated with a marked decrease in water intake behavior. These data suggest that the interaction between formaldehyde and AVP affects the water intake behaviors of mice. Furthermore, the highest concentration of formaldehyde in vivo was observed in the morning. Regular water intake is conducive to eliminating endogenous formaldehyde from the human body, particularly when water is consumed in the morning. Establishing good water intake habits not only effectively eliminates excess formaldehyde and other metabolic products but is also expected to yield valuable approaches to reducing the risk of AD prior to the onset of the disease.</p