Hydroxycinnamic acids do not prevent aortic atherosclerosis in hypercholesterolemic golden Syrian hamsters

The protective effect of hydroxycinnamic acids, i.e. caffeic acid (CA) and sinapic acid (SA) present in wine, and chlorogenic acid (CHA) present in apple, compared to a red wine phenolic extract (RWPE) was investigated in hamsters fed an atherogenic diet for 12 weeks. Five groups of 8 hamsters fed such a diet received by force-feeding RWPE, CA or SA in water, mimicking a moderate consumption of alcohol-free red wine. Controls received water and CHA force-feeding was extrapolated from apple consumption. Plasma cholesterol concentration was lower in group that received RWPE (-22%) and hydroxycinnamic acids had no effect. Plasma apolipoprotein Apo-A1 concentration was not affected; consumption of RWPE only decreased Apo-B concentration (-46%). Liver superoxide dismutase activity was 33% lower and glutathione peroxidase activity was 67% greater in the group receiving RWPE compared to controls; there was no effect when CA, SA or CHA were given. All the phenolic compounds significantly increased plasma antioxidant capacity (about 28% on average) compared with controls. Aortic fatty streak area was significantly reduced in the group receiving RWPE (-30%) in comparison with controls and hydroxycinnamic acids. Our findings demonstrate that chronic ingestion of the nonalcoholic components of red wine, mainly polyphenols, prevent the development of atherosclerosis in hamster and that wine hydroxycinnamic acids are not the phenolic compounds involved in such a beneficial effect.     

Cdk2 as a master of S phase entry: fact or fake?

It has long been believed that Cdk2 and its activator cyclin E play essential roles in the progression of the mitotic cell cycle. However, recent studies using knockout mouse models revealed that neither Cdk2 nor cyclin E are essential in vivo. The purpose of this Perspective is to compare both Cdk2 and cyclin E knockout mice models and to discuss potential mechanisms driving the cell cycle in the absence of Cdk2 or cyclin E. Particular emphasis is placed on possible non-catalytic roles of cyclin E, the expression and activity of the second cyclin binding partner of Cdk2, cyclin A, as well as on the expression and degradation of the Cdk2 inhibitor p27Kip1 in the absence of Cdk2.     

Antitumor agents. Part 236: Synthesis of water-soluble colchicine derivatives

Water-soluble colchicine derivatives were synthesized from 2-demethylcolchicine and 2-demethylthiocolchicine and evaluated in vitro against human tumor cell replication and for inhibition of tubulin polymerization. The glycinate esters (4, 5) and their tartaric acid salts (4a, 5a) showed potent cytotoxic activity in three different tumor cell lines with IC(50) values ranging from 0.02 to 0.88 microg/mL. The thiocolchicine analogs (5, 5a) were more potent than the colchicine analogs (4, 4a) in the tubulin polymerization assay. In particular, the water-soluble salt 5a merits preclinical development as an antitumor agent.     

Plants and animals: a different taste for microbes?

Plants and animals can recognize potential pathogens by detecting pathogen-associated molecular patterns (PAMPs). Significant advances over the past few years have begun to unveil the molecular basis of PAMP perception by pattern recognition receptors (PRRs). Although these discoveries highlight common recognition strategies among higher eukaryotes, they also show differences with respect to the nature of the receptors involved and the exact molecular patterns recognized. This suggests a convergent evolution of microbe sensing by the innate immune systems of these various organisms.     

Histone octamer instability under single molecule experiment conditions

We have studied the sample concentration-dependent and external stress-dependent stability of native and reconstituted nucleosomal arrays. Whereas upon stretching a single chromatin fiber in a solution of very low chromatin concentration the statistical distribution of DNA length released upon nucleosome unfolding shows only one population centered around approximately 25 nm, in nucleosome stabilizing conditions a second population with average length of approximately 50 nm was observed. Using radioactively labeled histone H3 and H2B, we demonstrate that upon lowering the chromatin concentration to very low values, first the linker histones are released, followed by the H2A-H2B dimer, whereas the H3-H4 tetramer remains stably attached to DNA even at the lowest concentration studied. The nucleosomal arrays reconstituted on a 5 S rDNA tandem repeat exhibited similar behavior. This suggests that the 25-nm disruption length is a consequence of the histone H2A-H2B dimer dissociation from the histone octamer. In nucleosome stabilizing conditions, a full approximately 145 bp is constrained in the nucleosome. Our data demonstrate that the nucleosome stability and histone octamer integrity can be severely degraded in experiments where the sample concentration is low.     

Insulin regulates ionic metabolism in a fresh water teleost, anabas testudineus (bloch)

Short term effects of insulin on total brain and branchial Na+K+ ATPase, Ca2+ ATPase and Na+, K+ and Ca2+ ions were investigated in A. testudineus. The increase in brain Ca2+ ATPase after alloxan treatment may account for an increased amount of intracellular calcium required for biochemical events taking place inside the cells. Branchial Na+K+ATPase was significantly stimulated while Ca2+ ATPase significantly inhibited after alloxan treatment. This suggests that alloxan exerts its inhibitory effect on the ATP-driven Ca2+ transport via; its action on the Ca2+ pump protein rather than the membrane permeability to Ca2+. The increased activity of brain Na+K+ ATPase at 3 and 24 hr by insulin to alloxan pretreated fish may account for the stimulated co-transport of glucose and its utilization for energy requirements and the excitatory action on neurons in the brain. The elevated brain Ca2+ ATPase may be due to the role of calcium as a second messenger in hormone action. At 24 hr, the activity of branchial Na+K+ ATPase and Ca2+ ATPase in alloxan pretreated specimens was significantly stimulated by insulin. This may be due to increased synthesis of these enzyme units. Administration of insulin (lU/fish) in normal fish significantly inhibited the activity of brain and branchial Na+K+ ATPase while brain Ca2+ ATPase showed a stimulatory effect at 3 and 24 hr compared to control. Inhibition of total branchial Ca2+ ATPase activity by insulin may be due to increased Ca2+ concentration. Higher plasma glucose level in alloxan treated groups confirms the diabetic effect of alloxan. Insulin reverses this effect. The possible mechanism by which insulin controls Na+K+ ATPase activity appears to be tissue specific. The results seem to be the first report on the effect of insulin on ATPase activity in a teleost. These data are consistent with the hypothesis that insulin performs a role in hydro mineral regulation in freshwater teleosts.     

Germline mutations of the paired-like homeobox 2B (PHOX2B) gene in neuroblastoma

Neuroblastoma (NB) is a frequent pediatric tumor for which recurrent somatic rearrangements are known. Germline mutations of predisposing gene(s) are suspected on the basis of rare familial cases and the association of NB with other genetically determined congenital malformations of neural crest-derived cells--namely, Hirschsprung disease (HSCR) and/or congenital central hypoventilation syndrome (CCHS). We recently identified the paired-like homeobox 2B (PHOX2B) gene as the major disease-causing gene in isolated and syndromic CCHS, which prompted us to regard it as a candidate gene in NB. Here, we report on germline mutations of PHOX2B in both a familial case of NB and a patient with the HSCR-NB association. PHOX2B, therefore, stands as the first gene for which germline mutations predispose to NB.     

Fas-mediated inhibition of CD4+ T cell priming results in dominance of type 1 CD8+ T cells in the immune response to the contact sensitizer trinitrophenyl

One of the unusual properties of chemically reactive haptens is their capacity to simultaneously generate immunogenic determinants for hapten-specific CD8(+) and CD4(+) T cells. Surprisingly, however, a clear dominance of CD8(+) effector T cells is observed in murine contact hypersensitivity to various haptens and upon T cell priming with hapten-modified APCs in vitro. In this study we show that trinitrophenyl-specific CD8(+) T cells actively prevent CD4(+) T cell priming in vitro. This process requires cell-cell contact and is dependent on the expression of Fas on the CD4(+) T cells. Our results reveal an important Fas-dependent mechanism for the regulation of hapten-specific CD4(+) T cell responses by CD8(+) T cells, which causes the dominance of CD8(+) effector T cells and the active suppression of a CD4(+) T cell response. Moreover, our demonstration of reduced contact hypersensitivity to trinitrophenyl in the absence of Fas, but not of perforin and/or granzymes A and B, underlines the important role of Fas as a pathogenetic factor for contact hypersensitivity.