Shielded geomagnetic field accelerates glucose consumption in human neuroblastoma cells by promoting anaerobic glycolysis.

A shielded geomagnetic field, also called the hypomagnetic field (HMF), interferes with the metabolic processes of various cells and animals exhibiting diverse effects in different models, however, its underlying mechanism remains largely unknown. In this study, we assessed the effect on the energy metabolism of SH-SY5Y cells in HMF and found that HMF-induced cell proliferation depends on glucose supply. HMF promoted SH-SY5Y cell proliferation by increasing glucose consumption rate via up-regulating anaerobic glycolysis in the cells. Increased activity of LDH, a key member of glycolysis, was possibly a direct response to HMF-induced cell proliferation. Thus, we unveiled a novel subcellular mechanism underlying the HMF-induced cellular response: the up-regulation of anaerobic glycolysis and repression of oxidative stress shifted cellular metabolism more towards the Warburg effect commonly observed in cancer metabolism. We suggest that cellular metabolic profiles of various cell types may determine HMF-induced cellular effects, and a magnetic field can be applied as a non-invasive regulator of cell metabolism.

Degradation of FA reduces Aß neurotoxicity and Alzheimer-related phenotypes.

Dysregulation of formaldehyde (FA) has been implicated in the development of Alzheimer's Disease (AD). Elevated FA levels in Alzheimer's patients and animal models are associated with impaired cognitive functions. However, the exact role of FA in AD remains unknown. We now identified that oxidative demethylation at serine8/26 of amyloid-beta protein (Aß) induced FA generation and FA cross-linked with the lysine28 residue in the ß-turn of Aß monomer to form Aß dimers, and then accelerated Aß oligomerization and fibrillogenesis in vitro. However, Aß42 mutation in serine8/26, lysine28 abolished Aß self-aggregation. Furthermore, Aß inhibited the activity of formaldehyde dehydrogenase (FDH), the enzyme for FA degradation, resulting in FA accumulation. In turn, excess of FA stimulated Aß aggregation both in vitro and in vivo by increasing the formation of Aß oligomers and fibrils. We found that degradation of FA by formaldehyde scavenger-NaHSO3 or coenzyme Q10 reduced Aß aggregation and ameliorated the neurotoxicity, and improved the cognitive performance in APP/PS1 mice. Our study provides evidence that endogenous FA is essential for Aß self-aggregation and scavenging FA could be an effective strategy for treating AD.

Urine D-ribose levels correlate with cognitive function in community-dwelling older adults.

BACKGROUND: D-ribose is involved in the pathogenesis of Alzheimer's Disease. The study aimed to determine the association between D-ribose and cognitive function in a sample of community-dwelling older adults. METHODS: A cross-sectional study was conducted in Chaoyang District, Beijing in 2019-2020. Eligible participants were community-based older adults aged 60 years and above. D-ribose was analyzed from the morning urine. Cognitive function, subjective cognitive decline, and depressive symptoms were measured by a battery of neuropsychological tests. Linear regressions were performed to determine the relationship between the urine D-ribose levels and cognitive performance. RESULTS: A sample of 1725 participants (67.1% female) aged 60 to 85 years (69.40 ± 5.87 years, mean ± SD) was enrolled in the analysis. The urine D-ribose concentrations ranged from 1.53 to 208.89 µmol/L (median 38.10 µmol/L; interquartile range 22.52-64.96 µmol/L). Higher levels of D-ribose were associated with worse performance on Mini-Mental State Examination and verbal fluency when age, gender, education, depressive symptoms, and cardiovascular risk factors were included as covariates. CONCLUSIONS: The urine D-ribose was negatively correlated with cognitive function in community-dwelling older adults. The findings suggest that the dysmetabolism of D-ribose may play a role at the early stage of cognitive impairment.

A rapid and non-invasive fluorescence method for quantifying coenzyme Q10 in blood and urine in clinical analysis.

BACKGROUND: Coenzyme Q10 (CoQ10) supplementation can improve cognition in patients with Alzheimer's disease (AD) and AD transgenic model mice. To ameliorate the discomfort that patients with AD suffer after several blood extractions, a non-invasive method for detecting urine CoQ10 levels needs to be established. METHODS: Here, we developed a new technique of fluorescence spectrophotometry with ethyl cyanoacetate (FS-ECA), on the basis of the principle that the chemical derivative obtained from the interaction between CoQ10 and ECA was detected by a fluorescence detector at λex/em  = 450/515 nm. As a standard reference method, the same batches of the clinical samples were analyzed by high-performance liquid chromatography with an ultraviolet detector (HPLC-UV) at 275 nm. RESULTS: The limits of detection (LOD) and limits of quantization (LOQ) (serum: 0.021 and 0.043 mg/L; urine: 0.012 and 0.025 mg/L) determined by the FS-ECA method were similar to that obtained through HPLC-UV (serum: 0.017 and 0.035 mg/L; urine: 0.012 and 0.025 mg/L). More importantly, this new FS-ECA technique as well as the conventional HPLC-UV method could detect a marked difference in urine CoQ10 levels between AD and controls. CONCLUSION: Our findings suggest that this non-invasive method for quantifying urine CoQ10 potentially replaces HPLC to detect blood CoQ10.

GRP78 protects CHO cells from ribosylation.

d-Ribose (Rib), a reactive glycation compound that exists in organisms, abnormally increases in the urine of diabetic patients and can yield large amounts of advanced glycation end products (AGEs), leading to cell dysfunction. However, whether cellular proteins are sensitive to this type of glycation is unknown. In this study, we found that cellular AGEs accumulate in Chinese hamster ovary (CHO) cells with increased Rib concentration and administration time. Mass spectrum analysis of isolated AGE-modified proteins from cell lysates showed that glucose-regulated protein 78 kD (GRP78) is one of the main ribosylated proteins. Co-immunoprecipitation assays further confirmed the interaction between AGEs and GRP78. Compared with d-glucose (Glc), Rib produced much more AGEs in cells. In kinetic studies, the first order rate constant of LDH released from CHO cells incubated with Rib was nearly 8-fold higher than that of Glc, suggesting that Rib is highly cytotoxic. Immunofluorescent co-localization analysis manifested partial superimposition of AGEs and GRP78, which were distributed throughout the endoplasmic reticulum. Western blotting showed that the expression of GRP78 is up-regulated and then down-regulated in CHO cells during Rib treatment. In the presence of Rib, the suppression of GRP78 expression either with transfected siRNA or with the inhibitor (-)-epigallocatechin gallate (EGCG) dramatically increased AGE levels and decreased cell viability compared with these parameters in the control groups. GRP78 overexpression decreased AGE levels and rescued the cells from Rib-induced cytotoxicity. These data indicate that GRP78 plays a role in preventing Rib-induced CHO cell cytotoxicity.

Hypomagnetic fields cause anxiety in adult male mice.

Hypomagnetic fields (HMF), that is, the elimination of the geomagnetic field (GMF), are a risk factor to the health of astronauts in outer space. It has been established that continuous HMF exposure affects cytoskeleton assembly, cell proliferation, embryonic development, and even learning and memory. In addition, although there were some previous studies that focused on the effects of long-term HMF-exposure, so far very limited investigations have been conducted to examine the short-term HMF effect in animals. In this study, we exposed adult male C57BL/6 mice to a 3-axis Helmholtz-coil HMF-simulation system for 72 h and found that short-term HMF-exposure induced a significant increase in anxiety-related behaviors. And our findings provide important information for both psychological intervention and the health care of astronauts. Bioelectromagnetics. 40:27-32, 2019. © 2018 Wiley Periodicals, Inc.

The fronto-insular cortex causally mediates the default-mode and central-executive networks to contribute to individual cognitive performance in healthy elderly.

The triple network model that consists of the default-mode network (DMN), central-executive network (CEN), and salience network (SN) has been suggested as a powerful paradigm for investigation of network mechanisms underlying various cognitive functions and brain disorders. A crucial hypothesis in this model is that the fronto-insular cortex (FIC) in the SN plays centrally in mediating interactions between the networks. Using a machine learning approach based on independent component analysis and Bayesian network (BN), this study characterizes the directed connectivity architecture of the triple network and examines the role of FIC in connectivity of the model. Data-driven exploration shows that the FIC initiates influential connections to all other regions to globally control the functional dynamics of the triple network. Moreover, stronger BN connectivity between the FIC and regions of the DMN and the CEN, as well as the increased outflow connections from the FIC are found to predict individual performance in memory and executive tasks. In addition, the posterior cingulate cortex in the DMN was also confirmed as an inflow hub that integrates information converging from other areas. Collectively, the results highlight the central role of FIC in mediating the activity of large-scale networks, which is crucial for individual cognitive function.

Decline of cell viability and mitochondrial activity in mouse skeletal muscle cell in a hypomagnetic field.

Hypomagnetic field (HMF), one of the key environmental risk factors for astronauts traveling in outer space, has previously been shown to repress locomotion of mammalians. However, underlying mechanisms of how HMF affects the motor system remains poorly understood. In this study, we created an HMF (<3 µT) by eliminating geomagnetic field (GMF, ∼50 µT) and exposed primary mouse skeletal muscle cells to this low magnetic field condition for a period of three days. HMF-exposed cells showed a decline in cell viability relative to GMF control, even though cells appeared normal in terms of morphology and survival rate. After a 3-day HMF-exposure, glucose consumption of skeletal muscle cells was significantly lower than GMF control, accompanied by less adenosine triphosphate (ATP) and adenosine diphosphate (ADP) content and higher ADP/ATP ratio. In agreement with these findings, mitochondrial membrane potential of HMF-exposed cells was also lower, whereas levels of cellular Reactive Oxygen Species were higher. Moreover, viability and membrane potential of isolated mitochondria were reduced after 1 h HMF-exposure in vitro. Our results indicate that mitochondria can directly respond to HMF at functional level, and suggest that HMF-induced decline in cell functionality results from a reduction in energy production and mitochondrial activity.

Formaldehyde induces hyperphosphorylation and polymerization of Tau protein both in vitro and in vivo.

BACKGROUND: Chronic formaldehyde exposure leads to memory impairment and abnormal elevation of endogenous formaldehyde has been found in the brains of Alzheimer's disease (AD) patients. Hyperphosphorylated Tau protein with subsequent aggregates as neurofibrillary tangles (NFTs) is one of the typical pathological characteristics in AD brains. The mechanism underlying abnormally elevated concentrations of endogenous formaldehyde that induce Tau hyperphosphorylation is unknown. METHODS: N2a cells and mice were treated with formaldehyde for different time points, then Western blotting and immunocytochemistry were utilized to determine the phosphorylation and polymerization of Tau protein. HPLC was used to detect the concentration of formaldehyde in cell media. RESULTS: Under formaldehyde stress, Tau became hyperphosphorylated, not only in the cytoplasm, but also in the nucleus of neuroblastoma (N2a) cells, and mouse brains. Polymers of cellular phospho-Tau were also detected. Significant accumulation of glycogen synthase kinase-3ß (GSK-3ß) in the nucleus of N2a and mouse brain cells, and elevation of its phosphorylation at Y216, was observed under formaldehyde stress. Formaldehyde-induced Tau hyperphosphorylation was blocked in the presence of LiCl and CT99021, inhibitors of GSK-3ß, and by RNAi interference. CONCLUSIONS: Formaldehyde, which may cause age-related memory loss, can act as a factor triggering Tau hyperphosphorylation via GSK-3ß catalysis and induces polymerization of Tau. GENERAL SIGNIFICANCE: Investigation of formaldehyde-induced Tau hyperphosphorylation may provide novel insights into mechanisms underlying tauopathies.

HDAC inhibition suppresses primary immune responses, enhances secondary immune responses, and abrogates autoimmunity during tumor immunotherapy.

Histone deacetylase inhibitors (HDACi) can modulate innate antiviral responses and render tumors more susceptible to oncolytic viruses (OVs); however, their effects on adaptive immunity in this context are largely unknown. Our present study reveals an unexpected property of the HDACi MS-275 that enhances viral vector-induced lymphopenia leading to selective depletion of bystander lymphocytes and regulatory T cells while allowing expansion of antigen-specific secondary responses. Coadministration of vaccine plus drug during the boosting phase focuses the immune response on the tumor by suppressing the primary immune response against the vaccine vector and enhancing the secondary response against the tumor antigen. Furthermore, improvement of T cell functionality was evident suggesting that MS-275 can orchestrate a complex array of effects that synergize immunotherapy and viral oncolysis. Surprisingly, while MS-275 dramatically enhanced efficacy, it suppressed autoimmune pathology, profoundly improving the therapeutic index.

Alternative Pre-mRNA Splicing, Cell Death, and Cancer.

Alternative splicing is one of the most powerful mechanisms for generating functionally distinct products from a single genetic loci and for fine-tuning gene activities at the post-transcriptional level. Alternative splicing plays important roles in regulating genes critical for cell death. These cell death genes encode death ligands, cell surface death receptors, intracellular death regulators, signal transduction molecules, and death executor enzymes such as caspases and nucleases. Alternative splicing of these genes often leads to the formation of functionally different products, some of which have antagonistic effects that are either cell death-promoting or cell death-preventing. Differential alternative splicing can affect expression, subcellular distribution, and functional activities of the gene products. Molecular defects in splicing regulation of cell death genes have been associated with cancer development and resistance to treatment. Studies using molecular, biochemical, and systems-based approaches have begun to reveal mechanisms underlying the regulation of alternative splicing of cell death genes. Systematic studies have begun to uncover the multi-level interconnected networks that regulate alternative splicing. A global picture of the complex mechanisms that regulate cell death genes at the pre-mRNA splicing level has thus begun to emerge.

MiR-124 regulates early neurogenesis in the optic vesicle and forebrain, targeting NeuroD1.

MicroRNAs (miRNAs) are involved in the fine control of cell proliferation and differentiation during the development of the nervous system. MiR-124, a neural specific miRNA, is expressed from the beginning of eye development in Xenopus, and has been shown to repress cell proliferation in the optic cup, however, its role at earlier developmental stages is unclear. Here, we show that this miRNA exerts a different role in cell proliferation at the optic vesicle stage, the stage which precedes optic cup formation. We show that miR-124 is both necessary and sufficient to promote cell proliferation and repress neurogenesis at the optic vesicle stage, playing an anti-neural role. Loss of miR-124 upregulates expression of neural markers NCAM, N-tubulin while gain of miR-124 downregulates these genes. Furthermore, miR-124 interacts with a conserved miR-124 binding site in the 3'-UTR of NeuroD1 and negatively regulates expression of the proneural marker NeuroD1, a bHLH transcription factor for neuronal differentiation. The miR-124-induced effect on cell proliferation can be antagonized by NeuroD1. These results reveal a novel regulatory role of miR-124 in neural development and uncover a previously unknown interaction between NeuroD1 and miR-124.

The protective effect of geniposide on human neuroblastoma cells in the presence of formaldehyde.

BACKGROUND: Formaldehyde can induce misfolding and aggregation of Tau protein and ß amyloid protein, which are characteristic pathological features of Alzheimer's disease (AD). An increase in endogenous formaldehyde concentration in the brain is closely related to dementia in aging people. Therefore, the discovery of effective drugs to counteract the adverse impact of formaldehyde on neuronal cells is beneficial for the development of appropriate treatments for age-associated cognitive decline. METHODS: In this study, we assessed the neuroprotective properties of TongLuoJiuNao (TLJN), a traditional Chinese medicine preparation, against formaldehyde stress in human neuroblastoma cells (SH-SY5Y cell line). The effect of TLJN and its main ingredients (geniposide and ginsenoside Rg1) on cell viability, apoptosis, intracellular antioxidant activity and the expression of apoptotic-related genes in the presence of formaldehyde were monitored. RESULTS: Cell counting studies showed that in the presence of TLJN, the viability of formaldehyde-treated SH-SY5Y cells significantly recovered. Laser scanning confocal microscopy revealed that the morphology of formaldehyde-injured cells was rescued by TLJN and geniposide, an effective ingredient of TLJN. Moreover, the inhibitory effect of geniposide on formaldehyde-induced apoptosis was dose-dependent. The activity of intracellular antioxidants (superoxide dismutase and glutathione peroxidase) increased, as did mRNA and protein levels of the antiapoptotic gene Bcl-2 after the addition of geniposide. In contrast, the expression of the apoptotic-related gene - P53, apoptotic executer - caspase 3 and apoptotic initiator - caspase 9 were downregulated after geniposide treatment. CONCLUSIONS: Our results indicate that geniposide can protect SH-SY5Y cells against formaldehyde stress through modulating the expression of Bcl-2, P53, caspase 3 and caspase 9, and by increasing the activity of intracellular superoxide dismutase and glutathione peroxidase.

The Protective Effect of Mangiferin on Formaldehyde-Induced HT22 Cell Damage and Cognitive Impairment.

Formaldehyde (FA) has been found to induce major Alzheimer's disease (AD)-like features including cognitive impairment, Aß deposition, and Tau hyperphosphorylation, suggesting that it may play a significant role in the initiation and progression of AD. Therefore, elucidating the mechanism underlying FA-induced neurotoxicity is crucial for exploring more comprehensive approaches to delay or prevent the development of AD. Mangiferin (MGF) is a natural C-glucosyl-xanthone with promising neuroprotective effects, and is considered to have potential in the treatment of AD. The present study was designed to characterize the effects and mechanisms by which MGF protects against FA-induced neurotoxicity. The results in murine hippocampal cells (HT22) revealed that co-treatment with MGF significantly decreased FA-induced cytotoxicity and inhibited Tau hyperphosphorylation in a dose-dependent manner. It was further found that these protective effects were achieved by attenuating FA-induced endoplasmic reticulum stress (ERS), as indicated by the inhibition of the ERS markers, GRP78 and CHOP, and downstream Tau-associated kinases (GSK-3ß and CaMKII) expression. In addition, MGF markedly inhibited FA-induced oxidative damage, including Ca2+ overload, ROS generation, and mitochondrial dysfunction, all of which are associated with ERS. Further studies showed that the intragastric administration of 40 mg/kg/day MGF for 6 weeks significantly improved spatial learning ability and long-term memory in C57/BL6 mice with FA-induced cognitive impairment by reducing Tau hyperphosphorylation and the expression of GRP78, GSK-3ß, and CaMKII in the brains. Taken together, these findings provide the first evidence that MGF exerts a significant neuroprotective effect against FA-induced damage and ameliorates mice cognitive impairment, the possible underlying mechanisms of which are expected to provide a novel basis for the treatment of AD and diseases caused by FA pollution.

Postoperative cognitive dysfunction is correlated with urine formaldehyde in elderly noncardiac surgical patients.

Post-operative cognitive dysfunction (POCD), especially in elderly patients, has been reported in many studies. Although increasing age, duration of anesthesia, postoperative infections, and respiratory complications were regarded as the risk factors for POCD, no extracerebral diagnostic biomarkers have been identified as indicators of POCD. Ninety-five patients, ages 65-80 years, scheduled for major orthopedic or abdominal surgery were enrolled. Twenty-two patients aged between 20 and 40 years undergoing the same procedures served as controls. Subjects received neuropsychological tests one-day prior and one week post procedure. To determine the presence of POCD, the criteria were used as described in most previous studies. Morning urine samples were obtained one day before surgery and on day 1, day 2 and day 7 post operatively. Urine formaldehyde was determined with high-performance liquid chromatography. The urine formaldehyde level of all patients with and without POCD increased on the first 2 days after surgery. But the formaldehyde concentration (on day 7) in patients with POCD was significantly higher than that in patients without POCD (p < 0.01). In the young control group, no patient was diagnosed with POCD. Although the changes in urine formaldehyde of young patients during perioperative period were similar to those in elderly patients without POCD, the formaldehyde concentrations measured at four time points were all significantly lower than those in elderly patients (p < 0.05). Levels of urine formaldehyde were elevated in the perioperative period, with the highest levels at day 7 in patients with POCD. This suggests that the increase on day 7 may provide a new physiologic marker along with neuropsychological assessments to assist in the diagnosis of POCD.

Altered development of Xenopus embryos in a hypogeomagnetic field.

The hypogeomagnetic field (HGMF; magnetic fields <200 nT) is one of the fundamental environmental factors of space. However, the effect of HGMF exposure on living systems remains unclear. In this article, we examine the biological effects of HGMF on the embryonic development of Xenopus laevis (African clawed frog). A decrease in horizontal third cleavage furrows and abnormal morphogenesis were observed in Xenopus embryos growing in the HGMF. HGMF exposure at the two-cell stage, but no later than the four-cell stage, is enough to alter the third cleavage geometry pattern. Immunofluorescent staining for α-tubulin showed reorientation of the spindle of four-cell stage blastomeres. These results indicate that a brief (2-h) exposure to HGMF is sufficient to interfere with the development of Xenopus embryos at cleavage stages. Also, the mitotic spindle could be an early sensor to the deprivation of the geomagnetic field, which provides a clue to the molecular mechanism underlying the morphological and other changes observed in the developing and/or developed embryos.

Correlation Between Urine Formaldehyde and Cognitive Abilities in the Clinical Spectrum of Alzheimer's Disease.

Urine-based formaldehyde has been reported to be a potential biomarker for Alzheimer's disease (AD). However, there is a lack of research about the correlation between urine formaldehyde and cognitive abilities in the clinical spectrum of AD, especially the preclinical period. The relationship of urine formaldehyde with APOE genotype, brain Aß status and plasma pathological markers in AD are also not clear. This study intends to explore the correlation between urine formaldehyde and cognitive abilities throughout the AD continuum, to evaluate the role of APOE genotype and Aß accumulation on urine formaldehyde, and further to clarify the relationship between urine formaldehyde level and AD plasma pathological markers. We recruited 72 cognitively normal controls (NC), 110 subjective cognitive decline (SCD), 140 objectively defined subtle cognitive decline (Obj-SCD), 171 mild cognitive impairment (MCI) and 136 AD dementia participants. Next, we collected the data of clinical materials, neuropsychological examination, APOE genotyping, urine formaldehyde concentration, 18F-florbetapir PET imaging and plasma biomarkers. Compared with NC, Obj-SCD and MCI groups, the level of urine formaldehyde was found to be significantly upregulated in SCD group. In addition, the level of urine formaldehyde was significantly higher in AD group compared to both NC and MCI groups. Further subgroup analysis showed that, the level of urine formaldehyde was higher in APOE ε4+ subgroup compared to APOE ε4- subgroup in both NC and AD groups. There was no difference in urine formaldehyde level between the brain Aß+ subgroup and Aß- subgroup in each group. In addition, regression analysis showed urine formaldehyde level was correlated with gender, plasma Aß42 and p-Tau181/T-tau. The dynamic change of urine formaldehyde in the AD continuum could be used as a potential biomarker, and combined with comprehensive cognitive evaluation could become a useful method to distinguish SCD from NC and Obj-SCD, and to distinguish MCI from AD.

Editors' roundup: October 2022.

This commentary constitutes the October edition of the 'Editors' roundup'-a multi-author omnibus of personal recommendations to interesting biophysics-related articles contributed by members of the editorial boards of leading international biophysics journals. The present commentary contains contributions from Progress in Biochemistry and Biophysics (an official journal of the Biophysical Society of China), European Biophysics Journal (the official journal of the European Biophysical Societies Association), Biophysical Reviews (the official IUPAB journal), and Biophysics (an official journal of the Russian Academy of Sciences). This edition of the Editors' Roundup also contains a new section from an editor at large who has provided selections from a number of journals on a single thematic topic.

Effect of ribose-glycated BSA on histone demethylation.

A reducing sugar reacts with the protein, resulting in advanced glycation end-products (AGEs), which have been implicated in diabetes-related complications. Recently, it has been found that both type 1 and type 2 diabetic patients suffer from not only glucose but also ribose dysmetabolism. Here, we compared the effects of ribose and glucose glycation on epigenetics, such as histone methylation and demethylation. To prepare ribose-glycated (riboglycated) proteins, we incubated 150 µM bovine serum albumin (BSA) with 1 M ribose at different time periods, and we evaluated the samples by ELISAs, Western blot analysis, and cellular experiments. Riboglycated BSA, which was incubated with ribose for approximately 7 days, showed the strongest cytotoxicity, leading to a significant decrease in the viability of SH-SY5Y cells cultured for 24 h (IC50 = 1.5 µM). A global demethylation of histone 3 (H3K4) was observed in SH-SY5Y cells accompanied with significant increases in lysine-specific demethylase-1 (LSD1) and plant homeodomain finger protein 8 (PHF8) after treatment with riboglycated BSA (1.5 µM), but demethylation did not occur after treatment with glucose-glycated (glucoglycated) proteins or the ribose, glucose, BSA, and Tris-HCl controls. Moreover, a significant demethylation of H3K4, H3K4me3, and H3K4me2, but not H3K4me1, occurred in the presence of riboglycated proteins. A significant increase of formaldehyde was also detected in the medium of SH-SY5Y cells cultured with riboglycated BSA, further indicating the occurrence of histone demethylation. The present study provides a new insight into understanding an epigenetic mechanism of diabetes mellitus (DM) related to ribose metabolic disorders.

Comparison of bovine serum albumin glycation by ribose and fructose in vitro and in vivo.

Advanced glycation end products (AGEs) play a critical pathogenic role in the development of diabetic complications. Recent studies have shown that diabetes is associated with not only abnormal glucose metabolism but also abnormal ribose and fructose metabolism, although glucose is present at the highest concentration in humans. The glycation ability and contribution of ribose and fructose to diabetic complications remain unclear. Here, the glycation ability of ribose, fructose and glucose under a mimic physiological condition, in which the concentration of ribose or fructose was one-fiftieth that of glucose, was compared. Bovine serum albumin (BSA) was used as the working protein in our experiments. Ribose generated more AGEs and was markedly more cytotoxic to SH-SY5Y cells than fructose. The first-order rate constant of ribose glycation was found to be significantly greater than that of fructose glycation. LC-MS/MS analysis revealed 41 ribose-glycated Lys residues and 12 fructose-glycated residues. Except for the shared Lys residues, ribose reacted selectively with 17 Lys, while no selective Lys was found in fructose-glycated BSA. Protein conformational changes suggested that ribose glycation may induce BSA into amyloid-like monomers compared with fructose glycation. The levels of serum ribose were correlated positively with glycated serum protein (GSP) and diabetic duration in type 2 diabetes mellitus (T2DM), respectively. These results indicate that ribose has a greater glycation ability than fructose, while ribose largely contributes to the production of AGEs and provides a new insight to understand in the occurrence and development of diabetes complications.