7 research outputs found
A Triazole Disulfide Compound Increases the Affinity of Hemoglobin for Oxygen and Reduces the Sickling of Human Sickle Cells
Sickle cell disease is an inherited
disorder of hemoglobin (Hb).
During a sickle cell crisis, deoxygenated sickle hemoglobin (deoxyHbS)
polymerizes to form fibers in red blood cells (RBCs), causing the
cells to adopt “sickled” shapes. Using small molecules
to increase the affinity of Hb for oxygen is a potential approach
to treating sickle cell disease, because oxygenated Hb interferes
with the polymerization of deoxyHbS. We have identified a triazole
disulfide compound (4,4′-diÂ(1,2,3-triazolyl)Âdisulfide, designated
TD-3), which increases the affinity of Hb for oxygen. The crystal
structures of carboxy- and deoxy-forms of human adult Hb (HbA), each
complexed with TD-3, revealed that one molecule of the monomeric thiol
form of TD-3 (5-mercapto-1H-1,2,3-triazole, designated MT-3) forms
a disulfide bond with β-Cys93, which inhibits the salt-bridge
formation between β-Asp94 and β-His146. This inhibition
of salt bridge formation stabilizes the R-state and destabilizes the
T-state of Hb, resulting in reduced magnitude of the Bohr effect and
increased affinity of Hb for oxygen. Intravenous administration of
TD-3 (100 mg/kg) to C57BL/6 mice increased the affinity of murine
Hb for oxygen, and the mice did not appear to be adversely affected
by the drug. TD-3 reduced in vitro hypoxia-induced sickling of human
sickle RBCs. The percentage of sickled RBCs and the <i>P</i><sub>50</sub> of human SS RBCs by TD-3 were inversely correlated
with the fraction of Hb modified by TD-3. Our study shows that TD-3,
and possibly other triazole disulfide compounds that bind to Hb β-Cys93,
may provide new treatment options for patients with sickle cell disease
Single Nucleotide Polymorphisms Associated with Cholelithiasis.
<p>Results of SNP association analysis with cholelithiasis in the CSSCD study using the additive model. The minor allele is the coded allele, and the OR is the odds for cholelithiasis in carriers of one extra copy of the coded allele.</p
Single Nucleotide Polymorphisms Associated with Total Bilirubin Levels.
<p>Genome wide significant SNPs in the CSSCD study and their replicates in the independent cohorts. The table reports the SNP identifier from dbSNP, chromosome, physical coordinates (hg18), the coded allele in PLINK (also minor allele) and the non-coded allele, the minor allele frequency (MAF) from the CSSCD cohort, the gene clusters where the SNP is located, and regression coefficientt and p-value in each study. Additive models of association were used in all studies. NA in the MSH means the SNP was unavailable in the 370 Illumina array.</p
Association Analysis with LDH, Reticulocyte Counts and Hemoglobin Concentration.
<p>Results of SNP association analysis with other hemolytic phenotypes including hemoglobin, LDH and reticulocyte count in the CSSCD Study.</p
LD Structure in the CSSCD Cohort.
<p>LD plots for regions in genes <i>UGT1A1, UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9</i> and <i>UGT1A10</i> on chromosome 2 in the CSSCD subjects. The LD plot was generated using Haploview 4.2. Each diamond represents the D’ value between two SNPs. The LD color scheme is: white D’<1 and LOD<2, blue D’ = 1 and LOD<2; shades of pinkish-red D’<1 and LOD≥2 and bright red D’ = 1 and LOD≥2.</p
Summary of the GWAS data from the CSSCD Cohort.
<p>The Manhattan plot (A) displays the –log10(p value) of the associations tested in the CSSCD cohort using the additive model. Color bands represent chromosomes, and SNPs are ordered by their physical position within each chromosome. The large spike in chromosome 2 corresponds to the <i>UGT1A1, UGT1A3, UGT1A8</i> and <i>UGT1A10</i> regions. The QQ-plot (B) displays the observed (y-axis) versus expected (x-axis) –log10 (p-value). From the QQ plot, there is minimal to no inflation in the test statistic.</p
Patient Characteristics in CSSCD, MSH and Walk-PHaSST cohorts.
*<p>Walk-PHaSST bilirubin measurement is in SI units.</p><p>Summary statistics of patient characteristics in the CSSCD, MSH, and WALK-PHaSSTstudies. For each study, the first column reports statistics (mean and standard deviation) for all patients included in the analysis and the second and third columns report statistics stratified by gender.</p