Curcumin induces senescence of primary human cells building the vasculature in a DNA damage and ATM-independent manner

Curcumin is considered not only as a supplement of the diet but also as a drug in many types of diseases and even as a potential anti-aging compound. It can reduce inflammation that increases with age and accompanies almost all age-related diseases. It has been suggested that curcumin can play a beneficial role in the cardiovascular system. However, there are also data showing that curcumin can induce senescence in cancer cells, which is a beneficial effect in cancer therapy but an undesirable one in the case of normal cells. It is believed that cellular senescence accompanies age-related changes in the cardiovascular system. The aim of this study was to check if curcumin, in a certain range of concentrations, can induce senescence in cells building the vasculature. We have found that human vascular smooth muscle and endothelial cells derived from aorta are very sensitive to curcumin treatment and can senesce upon treatment with cytostatic doses. We observed characteristic senescence markers but the number of DNA damage foci decreased. Surprisingly, in vascular smooth muscle cell (VSMC) activation of DNA damage response pathway downstream of ataxia-telangiectasia mutated (ATM) was observed. ATM silencing and the supplementation of antioxidants, N-acetyl-L-cysteine (NAC) or trolox, did not reduce the number of senescent cells. Thus, we have shown that curcumin can induce senescence of cells building the vasculature, which is DNA damage and ATM independent and is not induced by increased reactive oxygen species (ROS) level. We postulate that an increase in the bioavailability of curcumin should be introduced very carefully considering senescence induction as a side effect.

Electronic supplementary material

The online version of this article (doi:10.1007/s11357-014-9744-y) contains supplementary material, which is available to authorized users.     

Synthesis and Crystal Structure of Anhydrous Analog of 1,25-Dihydroxyvitamin D3

As predicted by single crystal X-ray crystallography, and contrary to the reported suggestions, the anhydrous form of calcipotriol, a therapeutically important vitamin D analog, was found stable enough to be used as an active pharmaceutical ingredient. The crystal and molecular structure of calcipotriol anhydrate was solved and refined using single crystal X-ray diffraction. The analog was obtained by a novel convergent synthesis from the vitamin D C-22 sulfone, as an advanced intermediate and a side-chain fragment. The homo-chiral side-chain aldehyde was obtained from cyclopropanecarboxyaldehyde by the chromatographic separation of the intermediate diastereomeric salts with (S)-naproxen. Calcipotriol anhydrate showed a single peak in differential scanning calorimetry and the absence of a peak from a water molecule, typical for the monohydrate. Calcipotriol anhydrate, as the only 1,25-dihydroxylated analog of vitamin D₃, exists as a mixture of both α- and β-forms of the A-ring, present in the asymmetric part of the unit cell of the crystal lattice. The intermolecular hydrogen bonding between both conformers in the crystal lattice indicated that the stability of calcipotriol anhydrate might be at least the same as for the known monohydrate. The usefulness of calcipotriol anhydrate as an active pharmaceutical ingredient was confirmed by the stability study in the standard conditions used for the storage of vitamin D analogs.     

The prevalence of waterpipe tobacco smoking among Polish youths

IntroductionWaterpipe smoking is gaining popularity among the youth in Poland and is evaluated for the first time in this work. The authors address the social and demographic factors that motivate young people to smoke and attempt to determine which of them contribute to habit formation.Material and methodsThe data were collected among school and university students in Poland during a global survey on various forms of tobacco use. Multivariable regression models were applied for odds-ratio evaluation. The data concern waterpipe and cigarette smoking habits.ResultsThe survey was completed by 19,097 respondents. The survey included 144 schools and 32 universities from 16 voivodeships in Poland. Respondent gender exhibited the highest ORs (95% Cl), both in the case of current and ever WP users: 2.11 (2.10–2.12) and 2.16 (2.15–2.17), respectively. The other important factor was a place of living: 1.83 (1.82–1.84) and 2.17 (2.16–2.18), respectively. All ORs were statistically significant for p = 0.05.ConclusionsThe prevalence of tobacco smoking among Polish youths is high. Waterpipe tobacco smoking was found to be the second most popular habit after cigarette smoking. Moreover, young smokers use other non-tobacco products in waterpipes, and drink alcohol during smoking sessions. Many young people try waterpipe smoking without previous experience with cigarettes.     

Trait anxiety and involuntary processing of facial emotions

There is suggestion that trait anxiety influences the processing of threat-related information. To test this hypothesis we recorded ERPs in response to subliminally presented and backward masked fearful and neutral faces, and non-face objects, in the preselected low- and high-anxious individuals. The amplitude of N170 was found to be larger when elicited by faces in comparison to non-faces, however it was not found to be emotion-sensitive or modulated by anxiety level. Differences between low- and high-anxious individuals appeared in a time window of the P1 component. At later stages, within the EPN component, stronger negativity specific for fearful faces was recorded exclusively in the low-anxious participants. Our findings indicate that anxiety level modulates early stages of information processing, as reflected in the P1 component. This leads to anxiety-related differences in involuntary emotional expression detection at later stages (EPN component).     

A role for KIR gene variants other than KIR2DS1 in conferring susceptibility to psoriasis

Recently we described an association between psoriasis and KIR2DS1, a gene for a stimulatory natural killer cell receptor, in a Polish population. The association was independently reported among Japanese and confirmed in a U.S. population. Prompted by these findings, we reanalyzed data by a multivariate approach in search of possible effects of KIR genes other than KIR2DS1 (non-KIR2DS1). The methodology was based on a stratified analysis and multiple logistic regression. We found that the non-KIR2DS1 genes had joint effects comparable to or stronger than the effects of KIR2DS1 in both the fraction of explained variance (0.174 vs 0.204, respectively, for KIR2DS1 and non-KIR2DS1) and the statistical significance (p = 0.000008 vs p = 0.000001, respectively). When individual genes were considered, a decrease in KIR2DS5 among patients vs controls (OR = 0.2, pcor = 0.0005) and a decrease in KIR2DS3 restricted to KIR2DS1-positive individuals (OR = 0.2, pcor = 0.005) were evident. We also performed a multivariate analysis of the HLA-Cw genotypes but failed to demonstrate any effects in addition to the known association with HLA-Cw*06. We conclude that the effect of the KIR genes on psoriasis susceptibility is complex, extending beyond the association with KIR2DS1 and involving protective effects and interactions.     

Highly potent 1-aminocyclohexane-1-carboxylic acid substituted V2 agonists of arginine vasopressin

The synthesis and some pharmacological properties of two sets of analogues, one consisting of six peptides with 1-aminocyclohexane-1-carboxylic acid (Acc) in position 2 and the other with the amino acid in position 3, have been described. All the peptides were tested for their pressor, antidiuretic, and uterotonic in vitro activities. The Acc(2) modification has been shown to selectively modulate the activities of the analogues. Four of the compounds were highly potent antidiuretic agonists with different pressor and uterotonic activities. On the other hand, the 3-substituted counterparts failed to exhibit any of the activities. One exception was provided by the [Mpa(1),Acc(3),Val(4),D-Arg(8)]VP analogue, which exhibited antidiuretic activity matching that of AVP, yet, unlike AVP, it was fairly selective.     

Diversity and function of the microbial community under strong selective pressure of rotifers

We unearthed some interesting microecological discoveries while selecting for the most beneficial bacterial strains to be used as probiotics in Lecane inermis rotifer mass culture. For 3 years, we maintained the cultures of L. inermis, with selection for the highest growth rate and resistance to potential contamination. Then, we conducted further selection and isolation in two groups: rotifers inoculated with the bacterial consortium isolated from the rotifer cultures, and rotifers fed with a commercial bioproduct. Selection was conducted in demanding conditions, with particulate matter suspended in spring water as a substrate, without aeration and under strong consumer pressure, and led to selection of two cultivable strains isolated from the optimal rotifers culture. According to molecular analysis, these strains were Aeromonas veronii and Pseudomonas mosselii. Biolog® ECO plate tests showed that both investigated bacterial communities metabolized wide but similar range of substrates. Therefore, intensely selective conditions led to considerable reduction in bacterial community regarding taxonomy, but not in metabolic activity, showing a functional composition decoupling. Aside from this result, our novel selection method dedicated to the sustainable culture of two trophic levels, a directed selection procedure (DSC), could potentially lead to the development of biotechnologically valuable strains with high metabolic activity and the ability to metabolize different sorts of substrate without harmful impact on higher trophic levels.     

Development and characterization of novel anti-C5 monoclonal antibodies capable of inhibiting complement in multiple species

Over the last decade there has been an explosion in complement therapies; one-third of the drugs in the clinic or in development target C5 protein. Eculizumab, a monoclonal antibody (mAb) that binds C5 and blocks its cleavage by the convertase, is the current reference standard treatment for atypical haemolytic uraemic syndrome (aHUS) and paroxysmal nocturnal haemoglobinuria (PNH) and in clinical trials for many other diseases. Here we describe a panel of novel anti-C5 mAb, including mAb that, like Eculizumab, are efficient inhibitors of complement but, unlike Eculizumab, inhibit across species, including human, rat, rabbit and guinea pig. Several inhibitory anti-C5 mAb were identified and characterized for C5 binding and lytic inhibitory capacity in comparison to current therapeutic anti-C5 mAb; three clones, 4G2, 7D4 and 10B6, were selected and further characterized for ligand specificity and affinity and cross-species inhibitory activity. The mAb 10B6 was human-specific whereas mAb 4G2 and 7D4 efficiently inhibited lysis by human, rabbit and rat serum, and weakly inhibited guinea pig complement; 7D4 also weakly inhibited mouse complement in vitro The rat C5-cross-reactive mAb 4G2, when administered intraperitoneally in a rat model of myasthenia gravis, effectively blocked the disease and protected muscle endplates from destruction. To our knowledge this is the first report of an anti-C5 function blocking mAb that permits preclinical studies in rats.