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1.  The correlations of glycated hemoglobin and carbohydrate metabolism parameters with heart rate variability in apparently healthy sedentary young male subjects 
Redox Biology  2015;5:301-307.
Sedentary lifestyle is a major risk factor for diabetes, cardiovascular and many other age-related diseases. Heart rate variability (HRV) reflects the function of regulatory systems of internal organs and may sensitively indicate early metabolic disturbances. We hypothesize that quantitative and qualitative changes of HRV in young subjects may reflect early metabolic derangements responsible for further development of clinically significant disease.
The aim of our study was to determine whether the parameters of carbohydrate metabolism (fasting blood glucose, HBA1c and surrogate insulin sensitivity/resistance indices) correlate with anthropometric data and HRV.
The study group consisted of 30 healthy sedentary male subjects aged 20–40, nonsmokers, mainly office and research employees, medical staff and students. Athletes, actively training more than one hour per week, severely obese and men of physical work were excluded from the study. HRV parameters were derived from short term ECG records (five minutes intervals) in supine position and during orthostatic test. Anthropometric data included height, weight, body mass index (BMI), age and body composition (estimation by bioelectric impedance method). The fasting blood glucose, insulin and C-peptide, homeostatic model assessment (HOMA-IR) index and glycated hemoglobin (HbA1c) were evaluated. Linear correlation coefficient (r) was calculated using Statistica 10.0 software.
Results and discussion
HOMA-IR index correlated positively with body weight, visceral fat and BMI (p=0.047, 0.027 and 0.017 respectively). In supine position pNN50 positively correlated with glucose/insulin ratio (p=0.011) and heart rate with HOMA-IR (p=0.006). In orthostatic test negative correlations of HBA1c with standard deviation, total and low frequency power were determined (p=0.034, 0.400 and 0.403 respectively), which indicates a gradual worsening of functional capacity of cardiovascular system with low-grade increase (under the conventional threshold) of HBA1c.
In apparently healthy sedentary subjects HRV reduction correlates with the age advancement, subclinical deteriorations of carbohydrate metabolism and excessive fat accumulation.
Graphical abstract
•Apparently healthy sedentary young male subjects were enrolled in the study.•HRV negatively correlates with age, BMI, visceral fat and insulin resistance.•Glycated hemoglobin negatively correlates with HRV parameters in orthostatic test.•Changes of HRV may reflect subclinical metabolic deteriorations in sedentary subjects.
PMCID: PMC4484544  PMID: 26092779
Sedentary lifestyle; Glycated hemoglobin; Heart rate variability; Insulin sensitivity; Correlations; ANS, autonomous nervous system; BMI, body mass index; CVS, cardiovascular system; ECG, electrocardiogram; FBG, fasting blood glucose; HBA1c, glycated hemoglobin; HF, the power of high frequency oscillations; HOMA, homeostatic model assessment; HR, heart rate; HRV, heart rate variability; HSS, healthy sedentary subjects; IR, insulin resistance; LF, the power of low frequency oscillations; OT, orthostatic test; pNN50, percentage of differences between adjacent normal RR intervals exceeding 50 milliseconds; RMSSD, square root of the mean squared differences of successive RR intervals; SAN, sinoatrial node; SDNN, standard deviation of normal RR intervals; TP, total power of RR-intervals oscillations; VLF, the power of very low frequency oscillations
2.  The novel endonuclease Ankle1 requires its LEM and GIY-YIG motifs for DNA cleavage in vivo 
Journal of cell science  2012;125(0 4):1048-1057.
The Lamina-associated polypeptide, Emerin, MAN1 - (LEM) domain defines a group of nuclear proteins, which bind chromatin through interaction of the LEM motif with the conserved DNA cross-linking protein, Barrier-to-Auto-Integration factor (BAF). Here, we describe a novel LEM protein, annotated in databases as “Ankyrin and LEM domain containing protein 1” (ANKLE1). We show that Ankle1 is conserved in metazoans and contains a unique C-terminal GIY-YIG motif that confers endonuclease activity in vitro and in vivo. In mammals, Ankle1 is predominantly expressed in hematopoietic tissues. While most characterized LEM proteins are components of the inner nuclear membrane, ectopic Ankle1 shuttles between cytoplasm and nucleus, and Ankle1 enriched in the nucleoplasm induces DNA cleavage and DNA damage response. This activity requires both the catalytic C-terminal GIY-YIG domain and the LEM motif, which binds chromatin via BAF. Hence, Ankle1 represents a novel LEM-protein with a GIY-YIG type endonuclease activity in higher eukaryotes.
PMCID: PMC4335191  PMID: 22399800
chromatin; DNA damage; GIY-YIG endonuclease; LEM-domain; nuclear envelope
3.  MSH3-Deficiency Initiates EMAST without Oncogenic Transformation of Human Colon Epithelial Cells 
PLoS ONE  2012;7(11):e50541.
Elevated microsatellite instability at selected tetranucleotide repeats (EMAST) is a genetic signature in certain cases of sporadic colorectal cancer and has been linked to MSH3-deficiency. It is currently controversial whether EMAST is associated with oncogenic properties in humans, specifically as cancer development in Msh3-deficient mice is not enhanced. However, a mutator phenotype is different between species as the genetic positions of repetitive sequences are not conserved. Here we studied the molecular effects of human MSH3-deficiency.
HCT116 and HCT116+chr3 (both MSH3-deficient) and primary human colon epithelial cells (HCEC, MSH3-wildtype) were stably transfected with an EGFP-based reporter plasmid for the detection of frameshift mutations within an [AAAG]17 repeat. MSH3 was silenced by shRNA and changes in protein expression were analyzed by shotgun proteomics. Colony forming assay was used to determine oncogenic transformation and double strand breaks (DSBs) were assessed by Comet assay.
Despite differential MLH1 expression, both HCT116 and HCT116+chr3 cells displayed comparable high mutation rates (about 4×10−4) at [AAAG]17 repeats. Silencing of MSH3 in HCECs leads to a remarkable increased frameshift mutations in [AAAG]17 repeats whereas [CA]13 repeats were less affected. Upon MSH3-silencing, significant changes in the expression of 202 proteins were detected. Pathway analysis revealed overexpression of proteins involved in double strand break repair (MRE11 and RAD50), apoptosis, L1 recycling, and repression of proteins involved in metabolism, tRNA aminoacylation, and gene expression. MSH3-silencing did not induce oncogenic transformation and DSBs increased 2-fold.
MSH3-deficiency in human colon epithelial cells results in EMAST, formation of DSBs and significant changes of the proteome but lacks oncogenic transformation. Thus, MSH3-deficiency alone is unlikely to drive human colon carcinogenesis.
PMCID: PMC3507781  PMID: 23209772
4.  Metabolism of the masked mycotoxin deoxynivalenol-3-glucoside in rats 
Toxicology Letters  2012;213(3):367-373.
► The metabolism of deoxynivalenol-3-glucoside (D3G) in rats was studied. ► Urine and feces were analyzed by a validated LC–MS/MS biomarker method. ► D3G was readily hydrolyzed to deoxynivalenol (DON) during digestion. ► Most D3G was metabolized by the gut microbiota and recovered in feces. ► D3G is of considerably lower toxicological relevance than DON, at least in rats.
Deoxynivalenol-3-β-d-glucoside (D3G), a plant metabolite of the Fusarium mycotoxin deoxynivalenol (DON), might be hydrolyzed in the digestive tract of mammals, thus contributing to the total dietary DON exposure of individuals. Yet, D3G has not been considered in regulatory limits set for DON for foodstuffs due to the lack of in vivo data. The aim of our study was to evaluate whether D3G is reactivated in vivo by investigation of its metabolism in rats. Six Sprague-Dawley rats received water, DON (2.0 mg/kg body weight (b.w.)) and the equimolar amount of D3G (3.1 mg/kg b.w.) by gavage on day 1, 8 and 15, respectively. Urine and feces were collected for 48 h and analyzed for D3G, DON, deoxynivalenol-glucuronide (DON-GlcA) and de-epoxy deoxynivalenol (DOM-1) by a validated LC–tandem mass spectrometry (MS/MS) based biomarker method. After administration of D3G, only 3.7 ± 0.7% of the given dose were found in urine in the form of analyzed analytes, compared to 14.9 ± 5.0% after administration of DON, and only 0.3 ± 0.1% were detected in the form of urinary D3G. The majority of administered D3G was recovered as DON and DOM-1 in feces. These results suggest that D3G is little bioavailable, hydrolyzed to DON during digestion, and partially converted to DOM-1 and DON-GlcA prior to excretion. Our data indicate that D3G is of considerably lower toxicological relevance than DON, at least in rats.
PMCID: PMC3448059  PMID: 22884771
D3G, deoxynivalenol-3-β-d-glucoside; DON, deoxynivalenol; JECFA, Joint FAO/WHO Expert Committee on Food Additives; DOM-1, de-epoxy deoxynivalenol; DON-GlcA, deoxynivalenol-glucuronide; DOM-1-GlcA, DOM-1-glucuronide; b.w., body weight; SPE, solid phase extraction; MeOH, methanol; ACN, acetonitrile; HPLC, high performance liquid chromatography; MS, mass spectrometry; MS/MS, tandem mass spectrometry; SRM, selected reaction monitoring; DP, declustering potential; CE, collision energy; RA, apparent recovery; SSE, signal suppression/enhancement; RE, recovery of the extraction step; LOD, limit of detection; LOQ, limit of quantification; Z14G, zearalenone-14-β-d-glucoside; Deoxynivalenol; Conjugated mycotoxins; ADME; Urine; Feces; Rodent
5.  Inhalative Exposure to Vanadium Pentoxide Causes DNA Damage in Workers: Results of a Multiple End Point Study 
Environmental Health Perspectives  2008;116(12):1689-1693.
Inhalative exposure to vanadium pentoxide (V2O5) causes lung cancer in rodents.
The aim of the study was to investigate the impact of V2O5 on DNA stability in workers from a V2O5 factory.
We determined DNA strand breaks in leukocytes of 52 workers and controls using the alkaline comet assay. We also investigated different parameters of chromosomal instability in lymphocytes of 23 workers and 24 controls using the cytokinesis-block micronucleus (MN) cytome method.
Seven of eight biomarkers were increased in blood cells of the workers, and vanadium plasma concentrations in plasma were 7-fold higher than in the controls (0.31 μg/L). We observed no difference in DNA migration under standard conditions, but we found increased tail lengths due to formation of oxidized purines (7%) and pyrimidines (30%) with lesion-specific enzymes (formamidopyrimidine glycosylase and endonuclease III) in the workers. Bleomycin-induced DNA migration was higher in the exposed group (25%), whereas the repair of bleomycin-induced lesions was reduced. Workers had a 2.5-fold higher MN frequency, and nucleoplasmic bridges (NPBs) and nuclear buds (Nbuds) were increased 7-fold and 3-fold, respectively. Also, apoptosis and necrosis rates were higher, but only the latter parameter reached statistical significance.
V2O5 causes oxidation of DNA bases, affects DNA repair, and induces formation of MNs, NPBs, and Nbuds in blood cells, suggesting that the workers are at increased risk for cancer and other diseases that are related to DNA instability.
PMCID: PMC2599764  PMID: 19079721
comet assay; cytokinesis-block micronucleus assay; DNA damage; occupational exposure; vanadium pentoxide

Results 1-5 (5)