Deferiprone: Pan-selective Histone Lysine Demethylase Inhibition Activity and Structure Activity Relationship Study

Deferiprone (DFP) is a hydroxypyridinone-derived iron chelator currently in clinical use for iron chelation therapy. DFP has also been known to elicit antiproliferative activities, yet the mechanism of this effect has remained elusive. We herein report that DFP chelates the Fe 2+ ion at the active sites of selected iron-dependent histone lysine demethylases (KDMs), resulting in pan inhibition of a subfamily of KDMs. Specifically, DFP inhibits the demethylase activities of six KDMs - 2A, 2B, 5C, 6A, 7A and 7B - with low micromolar IC 50 s while considerably less active or inactive against eleven KDMs - 1A, 3A, 3B, 4A-E, 5A, 5B and 6B. The KDM that is most sensitive to DFP, KDM6A, has an IC 50 that is between 7- and 70-fold lower than the iron binding equivalence concentrations at which DFP inhibits ribonucleotide reductase (RNR) activities and/or reduces the labile intracellular zinc ion pool. In breast cancer cell lines, DFP potently inhibits the demethylation of H3K4me3 and H3K27me3, two chromatin posttranslational marks that are subject to removal by several KDM subfamilies which are inhibited by DFP in cell-free assay. These data strongly suggest that DFP derives its anti-proliferative activity largely from the inhibition of a sub-set of KDMs. The docked poses adopted by DFP at the KDM active sites enabled identification of new DFP-based KDM inhibitors which are more cytotoxic to cancer cell lines. We also found that a cohort of these agents inhibited HP1-mediated gene silencing and one lead compound potently inhibited breast tumor growth in murine xenograft models. Overall, this study identified a new chemical scaffold capable of inhibiting KDM enzymes, globally changing histone modification profiles, and with specific anti-tumor activities

Isotopic diversity in interplanetary dust particles and preservation of extreme 16O-depletion

Two interplanetary dust particles (IDPs) investigated by NanoSIMS reveal diverse oxygen isotope compositions at the micrometre-scale. The oxygen isotope values recorded at different locations across the single IDP fragments cover a wider range than the bulk values available from all IDPs and bulk meteorites measured to date. Measurement of H, C, and N isotopes by NanoSIMS, and the use of scanning and transmission electron microscopy (SEM and TEM) to determine elemental compositions and textural information allows for a better understanding of the lithologies and organic signatures associated with the oxygen isotope features. IDP Balmoral, a ~15 μm-sized fragment with a chondritic porous (CP)-IDP-like texture, contains a region a few micrometres in size characterised by 16O-depleted isotope signatures in the range δ17O, δ18O = +80‰ to +200‰. The remainder of the fragment has a more 16O-rich composition (δ18O = 0–20‰), similar to many other IDPs and bulk meteorites. Other than in discrete pre-solar grains, such extreme 16O-depletions have only been observed previously in rare components within the matrix of the Acfer 094 meteorite. However, TEM imaging and FeO/MgO/Si ion ratios indicate that the 16O-depleted regions in Balmoral did not form by the same mechanism as that proposed for the 16O-depleted phases in Acfer 094. As the level of 16O depletion is consistent with that expected from isotope selective self-shielding, it is likely that the 16O-depleted reservoir was located close to that where oxygen self-shielding effects were most pronounced (i.e., the outer solar nebula or even interstellar medium). Individual regions within IDP Lumley cover a range in δ18O from −30‰ to +19‰, with the oxygen isotope values broadly co-varying with δD, δ13C, δ15N, light-element ratios and texture. The relationships observed in Lumley indicate that the parent body incorporated material at the micrometre-scale from discrete diverse isotopic reservoirs, some of which are represented by inner Solar System material but others which must have formed in the outer Solar System. The IDP fragments support a model whereby primary dust from the early solar nebula initially formed a variety of reservoirs in the outer solar nebula, with those at lower AU incorporating a higher proportion of inner Solar System chondritic dust than those at larger AU. These reservoirs were subsequently disrupted into micrometre-sized clasts that were re-incorporated into IDP parent bodies, presumably at large AU. These results reveal that any models accounting for mixing processes in the early solar nebula must also account for the presence of an extremely 16O-depleted reservoir in the comet-forming region

Chondrule fragments from Comet Wild2: evidence for high temperature processing in the outer Solar System

AbstractTerminal grains from C2063,1,154,1,0 (Track 154) and C2061,1,113,5 (Track 113) from the Stardust collection of Comet Wild2's coma have been studied by TEM and NanoSIMS. Terminal grain 2 of C2063,1,154,1,0 consists of an Al-rich diopside (En 97–99%, Al2O3 9–11wt%), pigeonite (En 85% Wo 15% with TiO2 and Al2O3 contents of 0.5 and 5.2wt%) and minor forsterite and enstatite. The mineral assemblage and Al-rich, Ti-poor composition of the grain are consistent with being a fragment of an Al-rich chondrule, similar to those present in carbonaceous chondrites. The oxygen isotopic composition of the C2063,1,154,1,0 grain was determined by NanoSIMS analyses and found to be δ17O −10.6±5.7‰, δ18O −7.5±2.5‰ and δ17O +1.4±4.3‰, δ18O −6.5±1.6‰ (1σ errors) for the two sections. These figures are distinct from CAIs and consistent with an origin as Al-rich chondrule fragments. Terminal grain 5 of C2061,1,113,5 consists of low Ca pyroxene En 86–87% Fs 10–11% Wo 3–4% and ≤2wt% Al2O3 and in one section 5–10% of a Na-rich silicate phase. This assemblage may be a fragment of a low-Ca pyroxene-bearing chondrule and mesostasis. The original chondrule diameter for the C2063,1,154,1,0 and C2061,1,113,5 samples, by analogy with carbonaceous chondrite chondrules, might have been in the range 0.2–1.0mm. If they were of that size, then the presence of large grains of high temperature material (e.g. ≥1500K for such refractory assemblages) could be explained through commonly invoked models of radial drift from inner to outer Solar System, but only if the chondrules were first fragmented to dust within the inner Solar System. An alternative scenario is that some chondrule formation was associated with high temperature processing and planetesimals in the outer Solar System

Parallel nocturnal secretion of melatonin and testosterone in the plasma of normal men

Differences and similarities in the temporal organization of hormone secretion in plasma reflect the activity of CNS pacemakers. One aspect of this activity, the temporal synchronization of the secretion of different hormones is still poorly understood. We report the analysis of melatonin and testosterone plasma concentrations during two nights in 6 normal healthy young men. Blood was collected every 20 min between 2040 and 0640. Plasma testosterone concentrations increased by 1.5- to 2- fold during the second part of the night, and melatonin by 2.5-to 4-fold. In each subject. the individual temporal pattern of melatonin was quite stable over the two nights of sampling. while testosterone profiles showed fluctuations. There was a high degree of parallelism in these two hormones nocturnal secretion. These results, together with previous studies, suggest that melatonin might entrain the nocturnal secretion of testosteron