Genetic variation associated with chromosomal aberration frequency: A genome-wide association study

Chromosomal aberrations (CAs) in human peripheral blood lymphocytes (PBL) measured with the conventional cytogenetic assay have been used for human biomonitoring of genotoxic exposure for decades. CA frequency in peripheral blood is a marker of cancer susceptibility. Previous studies have shown associations between genetic variants in metabolic pathway, DNA repair and major mitotic checkpoint genes and CAs. We conducted a genome-wide association study on 576 individuals from the Czech Republic and Slovakia followed by a replication in two different sample sets of 482 (replication 1) and 1288 (replication 2) samples. To have a broad look at the genetic susceptibility associated with CA frequency, the sample sets composed of individuals either differentially exposed to smoking, occupational/environmental hazards, or they were untreated cancer patients. Phenotypes were divided into chromosome- and chromatid-type aberrations (CSAs and CTAs, respectively) and total chromosomal aberrations (CAtot). The arbitrary cutoff point between individuals with high and low CA frequency was 2% for CAtot and 1% for CSA and CTA. The data were analyzed using age, sex, occupation/cancer and smoking history as covariates. Altogether 11 loci reached the P-value of 10⁻⁵ in the GWAS. Replication 1 supported the association of rs1383997 (8q13.3) and rs2824215 (21q21.1) in CAtot and rs983889 (5p15.1) in CTA analysis. These loci were found to be associated with genes involved in mitosis, response to environmental and chemical factors and genes involved in syndromes linked to chromosomal abnormalities. Identification of new genetic variants for the frequency of CAs offers prediction tools for cancer risk in future. Environ. Mol. Mutagen. 60:17–28, 2019. © 2018 Wiley Periodicals, Inc.     

Herbal polysaccharides and cough reflex

In the last decades plant substances have become a leading form of treatment of many respiratory symptoms, including cough. It has been shown that compounds purified form polysaccharides from Adhatoda vasica, Withania somnifera, and Glycyrrhiza glabra have various biological activities, such as antioxidant, anti-inflammatory, immunomodulating, antispasmodic action, or antiallergic properties, and they often act as cough suppressants. This work demonstrates new natural substitutes for synthetic antitussives whose application is associated with numerous adverse effects. We investigated pharmacodynamic characteristics of arabinogalacatan samples extracted from A. vasica, W. somnifera, and G. glabra. These extracts showed the ability to reduce citric acid-induced cough in awake guinea pigs after oral administration in a dose of 50 mg/kg. The strongest antitussive effect (81%) was found after application of the extract from G. glabra. There was a 67% cough suppression with A. vasica and 61% with W. somnifera, which was comparable with the antitussive activity of codeine (62%).     

Elevated heart rate and nondipping heart rate as potential targets for melatonin: a review

Elevated heart rate is a risk factor for cardiovascular and all‐cause mortalities in the general population and various cardiovascular pathologies. Insufficient heart rate decline during the night, that is, nondipping heart rate, also increases cardiovascular risk. Abnormal heart rate reflects an autonomic nervous system imbalance in terms of relative dominance of sympathetic tone. There are only a few prospective studies concerning the effect of heart rate reduction in coronary heart disease and heart failure. In hypertensive patients, retrospective analyses show no additional benefit of slowing down the heart rate by beta‐blockade to blood pressure reduction. Melatonin, a secretory product of the pineal gland, has several attributes, which predict melatonin to be a promising candidate in the struggle against elevated heart rate and its consequences in the hypertensive population. First, melatonin production depends on the sympathetic stimulation of the pineal gland. On the other hand, melatonin inhibits the sympathetic system in several ways representing potentially the counter‐regulatory mechanism to normalize excessive sympathetic drive. Second, administration of melatonin reduces heart rate in animals and humans. Third, the chronobiological action of melatonin may normalize the insufficient nocturnal decline of heart rate. Moreover, melatonin reduces the development of endothelial dysfunction and atherosclerosis, which are considered a crucial pathophysiological disorder of increased heart rate and pulsatile blood flow. The antihypertensive and antiremodeling action of melatonin along with its beneficial effects on lipid profile and insulin resistance may be of additional benefit. A clinical trial investigating melatonin actions in hypertensive patients with increased heart rate is warranted.     

GABAA/benzodiazepine receptor α6 subunit mRNA in granule cells of the cerebellar cortex and cochlear nuclei: Expression in developing and mutant mice

The gamma aminobutyric acid_A/benzodiazepine (GABA_A/BZ) receptor is a multisubunit (α, β, γ, δ, and ρ) ligand-gated chloride channel; there are several variants of the α, β, and γ subunits, each of which has been localized throughout the central nervous system. A large number of GABA_A/BZ subunit variants are expressed within the cerebellar cortex. In previous studies from other laboratories, α₆ subunit mRNA has been reported to be present exclusively in cerebellar granule cells. The developmental expression of α₆ mRNA in cerebellar and cochlear granule cells is of interest because it has been suggested that each of these cell types is derived from a common precursor pool. The polymerase chain reaction was used to generate a cDNA fragment encoding a portion of the M3–M4 intracellular loop of the α₆ subunit of the GABA_A/BZ receptor. A [³⁵S] riboprobe, transcribed from this cDNA fragment, was used to examine the expression of the α₆ subunit mRNA by in situ hybridization in developing normal mice and in adult mutant mice with known deficits in synaptic circuitry. A strong hybridization signal was observed over the granule cell layers of both the cerebellum and cochlear nuclei in adult mice. The signal over the cochlear nuclei appeared after birth toward the end of postnatal week 1, coinciding with the appearance of labeling in the cerebellar cortex. The intensity of the hybridization signal in both regions increased rapidly until postnatal day 14, after which it increased more gradually, reaching adult levels during postnatal week 3. In the weaver mutant, α₆ labeling was detected in surviving granule cells, but not in cerebellar regions devoid of granule cells. Significant levels of the α₆ hybridization signal were also present in cerebellar granule cells of Purkinje cell degeneration, lurcher, and staggerer mutants, suggesting that aberrations in synaptic circuitry do not prevent α₆ subunit gene expression. Our results demonstrate that α₆ subunit mRNA is not limited to the cerebellum, but is expressed in other neurons which share a common cellular precursor pool. These data also suggest that these granule cell precursors may be intrinsically programmed to acquire a specific form of the GABA_A/BZ receptor, irrespective of their final location and lack of connections with target neurons. © 1994 Wiley-Liss, Inc.     

Evidence that the lateral septum is involved in the antidepressant-like effects of the vasopressin V1b receptor antagonist, SSR149415.

Previous experiments with the first selective nonpeptide vasopressin V1b receptor antagonist SSR149415 ((2S, 4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide) have shown that the drug elicits anxiolytic- and antidepressant-like effects following systemic administration. Extrahypothalamic V1b receptors have been suggested to be involved in these effects as evidenced by the findings that hypophysectomized rats were still sensitive to the antistress action of SSR149415. The first objective of the present work aimed at locating V1b receptors in the rat limbic brain using anti-V1b receptor immunohistochemistry. The immunolabeling revealed high densities of V1b receptors in the lateral septum, the amygdala, the bed nucleus of the stria terminalis, the hippocampal formation, and in several cortical areas. Since the lateral septum is well known to participate in the modulation of emotional processes, the second objective of this study went on to evaluate the behavioral effects of an infusion of SSR149415 into the lateral septum and to determine whether its behavioral effects are mediated by this structure. Animals were tested in models classically used for the screening of anxiolytics (ie the punished drinking and elevated plus-maze tests) and antidepressants (ie the forced-swimming test). Bilateral intraseptal infusion of SSR149415 (10 and 100 ng) produced a decrease in immobility time in the forced-swimming test, indicating antidepressant-like effects. In contrast, the behavior of rats in the punished drinking procedure or in the elevated plus-maze test was not modified by intraseptal infusion of SSR149415. These findings suggest that V1b receptors located in the lateral septum participate in the antidepressant- but not the anxiolytic-like action of SSR149415 in rats.     

Markers of individual susceptibility and DNA repair rate in workers exposed to xenobiotics in a tire plant

Workers employed in tire plants are exposed to a variety of xenobiotics, such as 1,3-butadiene (BD), soots containing polycyclic aromatic hydrocarbons, and other organic chemicals (e.g., styrene). In the present study, we investigated markers of genotoxicity [chromosomal aberrations (CAs) and single-strand breaks (SSBs)] in a cohort of 110 tire plant workers engaged in jobs with different levels of xenobiotic exposure in relation to various polymorphisms in genes coding for biotransformation enzymes (CYP1A1, CYP2E1, EPHX1, GSTM1, GSTP1, and GSTT1) and in genes involved in DNA repair (XPD exon 23, XPG exon 15, XPC exon 15, XRCC1 exon 10, and XRCC3 exon 7). In addition, the expression of CYP2E1, a gene playing a key role in BD metabolism, was determined by real-time PCR in peripheral blood lymphocytes, and the capacity of lymphocytes to repair gamma-ray-induced SSBs and to convert 8-oxoguanine in HeLa cell DNA into SSBs was assessed using in vitro assays. No positive associations were detected between the CA frequency or SSB induction and levels of workplace exposure; however, a nonsignificant twofold higher irradiation-specific DNA repair rate was found among highly exposed workers. In evaluations conducted with the markers of individual susceptibility, workers with low-EPHX1-activity genotypes exhibited a significantly higher CA frequency as compared to those with medium and high-EPHX1-activity genotypes (P = 0.050). CA frequencies were significantly lower in individuals homozygous for the XPD exon 23 variant allele in comparison to those with the wild-type CC genotype (P = 0.003). Interestingly, CAs were higher in individuals with higher CYP2E1 expression levels, but the association was nonsignificant (P = 0.097). The results from this study suggest the importance of evaluating markers of individual susceptibility, since they may modulate genotoxic effects induced by occupational exposure to xenobiotics.