Ketoconazole inhibits developmental activation of <i>Strongyloides stercoralis</i> iL3 in host-like culture conditions; this inhibition is rescued by Δ7-dafachronic acid.
Mennatallah M. Y. Albarqi
Jonathan D. Stoltzfus
Adeiye A. Pilgrim
Thomas J. Nolan
Zhu Wang
Steven A. Kliewer
David J. Mangelsdorf
James B. Lok
10.1371/journal.ppat.1005358.g005
https://plos.figshare.com/articles/figure/_Ketoconazole_inhibits_developmental_activation_of_Strongyloides_stercoralis_iL3_in_host_like_culture_conditions_this_inhibition_is_rescued_by_7_dafachronic_acid_/1632489
<p>Frequency of feeding by cultured larvae, as reflected by ingestion of fluorescein isothiocyanate (FITC), was used as an index of developmental activation of infectious third-stage larvae (iL3). Larval mortality was scored as the percentage of larvae classed as non-motile and therefore “dead.” (A) Frequency of iL3 feeding and larval mortality as a function of ketoconazole concentration in Dulbecco’s modified Eagle’s Medium (DMEM), a permissive culture medium. DMEM without ketoconazole was the positive control. M9 buffer, a non-permissive medium, was used without ketoconazole as the negative control. ** Negative correlation of iL3 feeding and ketoconazole concentration (bracketed) is significant (P = 0.0028; Spearman r = -1.000). (B) Frequency of iL3 feeding and larval mortality as a function of Δ7-dafachronic acid (Δ7-DA) concentration in DMEM cultures containing an inhibitory concentration of ketoconazole (35 μM). Cultures of larvae in DMEM alone or in DMEM with 800 nM Δ7-DA were positive controls. Cultures of larvae in M9 buffer constituted the negative control. * Positive correlation of iL3 feeding in 35 μM ketoconazole and Δ7-DA concentration (bracketed) is significant (P = 0.0167; Spearman r = 1.000). In both panels, bar heights represent the mean percentage of iL3 feeding (blue bars) or the mean percentage of dead iL3 (white bars) in four biological replicates. Error bars indicate +1 standard deviation.</p>
2016-01-05 14:56:13
CYP inhibitor ketoconazole
1 μ M Δ7- DA
post-parasitic first-stage larvae
post-parasitic L 1s
iL 3 activation
400 nM Δ7- DA
nematode Strongyloides stercoralis
hormone receptor DAF -12. Biosynthesis
DAF -9.
35 μ M ketoconazole
26 CYP-encoding genes
free-living nematode Caenorhabditis elegans
DAF -12
iL 3 arrest
DA production
SD
Δ7- DA exposure
40 μ M ketoconazole
stercoralis development
iL 3
cytochrome P 450
post-free-living iL 3 arrest
Life Cycle Checkpoints