8 research outputs found
Factors influencing H1N1 vaccine behavior among Manitoba Metis in Canada: a qualitative study
3-Hydroxypropionic Acid and Methylcitric Acid Are Not Reliable Indicators of Marginal Biotin Deficiency in Humans
Indicators of marginal biotin deficiency and repletion in humans: validation of 3-hydroxyisovaleric acid excretion and a leucine challenge
Urinary Excretion of 3-Hydroxyisovaleryl Carnitine Is an Early and Sensitive Indicator of Marginal Biotin Deficiency in Humans12
Mounting evidence indicates that marginal biotin deficiency is not rare, contrary to previous assumptions. Accordingly, robust indicators of biotin status would be useful. In a study of 10 healthy adults, we recently provided evidence that abnormally increased plasma concentration of 3-hydroxyisovaleryl carnitine (3HIA-carnitine) is a sensitive indicator of marginal biotin deficiency. We sought to determine whether urinary excretion of 3HIA-carnitine (expressed as the ratio to urinary creatinine) significantly increases in marginal biotin deficiency. Marginal, asymptomatic biotin deficiency was induced experimentally in the same 10 healthy adults (8 women) by feeding undenatured egg white with meals for 28 d. Biotin status was repleted by a mixed general diet plus biotin supplementation. Urinary excretion of 3HIA-carnitine was determined by liquid chromatography-tandem MS on d 0, 14, and 28 (depletion) and on d 35 and 50 (repletion). Mean urinary 3HIA-carnitine concentration increased with depletion (P < 0.0001; d 0 vs. 28) and decreased with repletion (P = 0.0002; d 28 vs. 50). Urinary 3HIA-carnitine excretion was greater than the upper limit of normal in 9 of 10 participants by d 14 and decreased to within normal limits by d 50 in all participants. This study provides evidence that urinary excretion of 3HIA-carnitine is an early and sensitive indicator of marginal biotin deficiency. The ease of collection of untimed urine samples and application of a new analytical method with simplified sample preparation suggest that urinary 3HIA-carnitine is likely to be a useful indicator for large population studies
Plasma concentration of 3-hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal biotin deficiency in humans1234
Background: Blood-based indicators of biotin status in humans were shown to be useful tools in several clinical situations, including pregnancy. We previously validated the activity of the biotin-dependent enzyme propionyl-coenzyme A carboxylase (PCC) in lymphocytes as a sensitive and specific blood-based indicator of marginal degrees of biotin deficiency. However, the measurement of PCC activity in population studies presents substantial analytic challenges. 3-Hydroxyisovaleryl carnitine (3HIA-carnitine) increases in response to the decreased activity of the biotin-dependent enzyme methylcrotonyl-coenzyme A carboxylase and might reflect biotin status
Screening and Biological Effects of Marine Pyrroloiminoquinone Alkaloids: Potential Inhibitors of the HIF-1α/p300 Interaction
Inhibition of the hypoxia-inducible
factor 1α (HIF-1α) pathway by disrupting its association
with the transcriptional coactivator p300 inhibits angiogenesis and
tumor development. Development of HIF-1α/p300 inhibitors has
been hampered by preclinical toxicity; therefore, we aimed to identify
novel HIF-1α/p300 inhibitors. Using a cell-free assay designed
to test compounds that block HIF-1α/p300 binding, 170 298
crude natural product extracts and prefractionated samples were screened,
identifying 25 active extracts. One of these extracts, originating
from the marine sponge <i>Latrunculia</i> sp., afforded
six pyrroloiminoquinone alkaloids that were identified as positive
hits (IC<sub>50</sub> values: 1–35 μM). Luciferase assays
confirmed inhibition of HIF-1α transcriptional activity by discorhabdin
B (<b>1</b>) and its dimer (<b>2</b>), 3-dihydrodiscorhabdin
C (<b>3</b>), makaluvamine F (<b>5</b>), discorhabdin
H (<b>8</b>), discorhabdin L (<b>9</b>), and discorhabdin
W (<b>11</b>) in HCT 116 colon cancer cells (0.1–10 μM, <i>p</i> < 0.05). Except for <b>11</b>, all of these compounds
also reduced HIF-1α transcriptional activity in LNCaP prostate
cancer cells (0.1–10 μM, <i>p</i> < 0.05).
These effects occurred at noncytotoxic concentrations (<50% cell
death) under hypoxic conditions. At the downstream HIF-1α target
level, compound <b>8</b> (0.5 μM) significantly decreased
VEGF secretion in LNCaP cells (<i>p</i> < 0.05). In COLO
205 colon cancer cells no activity was shown in the luciferase or
cytotoxicity assays. Pyrroloiminoquinone alkaloids are a novel class
of HIF-1α inhibitors, which interrupt the protein–protein
interaction between HIF-1α and p300 and consequently reduce
HIF-related transcription