No abstract

Beryllium has multiple industrial applications, but its manufacture is associated with a serious occupational risk of developing chronic inflammation in the lungs known as berylliosis, or chronic beryllium disease. Although the Be-induced abnormal immune responses have recently been linked to a specific MHC-II allele, the nature of long-lasting granulomas is not fully understood. Here we show that Be binds with a micromolar affinity to phosphatidylserine (PS), the major surface marker of apoptotic cells. Isothermal titration calorimetry indicates that, like that of Ca, binding of Be to PS liposomes is largely entropically driven, likely by massive desolvation. Be exerts a compacting effect on PS monolayers, suggesting cross-linking through coordination by both phosphates and carboxyls in multiple configurations, which were visualized in molecular dynamics simulations. Electrostatic modification of PS membranes by Be includes complete neutralization of surface charges at ∼30 μM, accompanied by an increase in the boundary dipole potential. The data suggest that Be can displace Ca from the surface of PS, and being coordinated in a tight shell of four oxygens, it can mask headgroups from Ca-mediated recognition by PS receptors. Indeed, 48 μM Be added to IC-21 cultured macrophages specifically suppresses binding and engulfment of PS-coated silica beads or aged erythrocytes. We propose that Be adsorption at the surface of apoptotic cells may potentially prevent normal phagocytosis, thus causing accumulation of secondary necrotic foci and the resulting chronic inflammation.

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Cataract formation represents a serious problem in the elderly and has a large impact on healthcare budget. Aging and cataract formation are relatively complex phenomena, both in vivo and in vitro. Telomeres are special structures at the end of chromosomes. They shorten during each round of replication, and this has been characterized as a mitotic counting mechanism. Our review analysis in this work shows that the rate of telomere shortening in human lens epithelial cells during aging and cataract formation is modulated by oxidative stress as well as by differences in antioxidative defense capacity of the normal and cataractous crystalline lenses. Presented in this review studies suggest that telomere shortening in human lens cells and increased oxidative stress are the result of the peroxidative damage to the lens cell membranes and biomolecules induced in the lack of reductive detoxification of phospholipid hydroperoxides as the triggering mechanism of cataractogenesis. Lipid peroxidation (LPO) is a causative factor of cataract. The increased concentrations of primary molecular LPO products (diene conjugates, lipid hydroperoxides) and end fluorescent LPO products were detected in the lipid moieties of the aqueous humor samples obtained from patients with senile and complicated cataracts when compared to normal donors. The progressive accumulation of oxidative damage may act as an important mechanism for organism aging and cataractogenesis. The oxidative stress form and intensity might determine the lens senescence rate and cataract type, making efforts in the cataract prevention challenge more complex. The analyzed challenge in this work is that the reduction in telomere shortening rate and damages in telomeric DNA make an important contribution to the anticataract and life-extension effect of carnosine administered systemically in the formulations stabilizing a dipeptide from the enzymatic hydrolysis with carnosinase, or topically administered to the eye with carnosine ophthalmic prodrug N-acetylcarnosine and lubricant formulations thereof including corneal absorption promoters. Telomere length in the human crystalline lens cells is a reflection of aging, cataractogenesis, and lifespan in biogerontological studies.

BackgroundCarotid body tumor (CBT) is a form of head and neck paragangliomas (HNPGLs) arising at the bifurcation of carotid arteries. Paragangliomas are commonly associated with germline and somatic mutations involving at least one of more than thirty causative genes. However, the specific functionality of a number of these genes involved in the formation of paragangliomas has not yet been fully investigated.MethodsExome library preparation was carried out using Nextera® Rapid Capture Exome Kit (Illumina, USA). Sequencing was performed on NextSeq 500 System (Illumina).ResultsExome analysis of 52 CBTs revealed potential driver mutations (PDMs) in 21 genes: ARNT, BAP1, BRAF, BRCA1, BRCA2, CDKN2A, CSDE1, FGFR3, IDH1, KIF1B, KMT2D, MEN1, RET, SDHA, SDHB, SDHC, SDHD, SETD2, TP53BP1, TP53BP2, and TP53I13. In many samples, more than one PDM was identified. There are also 41% of samples in which we did not identify any PDM; in these cases, the formation of CBT was probably caused by the cumulative effect of several not highly pathogenic mutations. Estimation of average mutation load demonstrated 6–8 mutations per megabase (Mb). Genes with the highest mutation rate were identified.ConclusionsExome analysis of 52 CBTs for the first time revealed the average mutation load for these tumors and also identified potential driver mutations as well as their frequencies and co-occurrence with the other PDMs.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0327-0) contains supplementary material, which is available to authorized users.