1. Classification
1.1. Inherited
1.1.1. Qualitative
1.1.1.1. Sickle cell disease (SCD) --- Glu to Val (hydrophobic) (HbS) --- At low oxygen --- polymerization --- malfunction to bind oxygen, generate superoxide, damage cytoskeleton, dehydration (K:Cl co-transporter) --- increase hemolysis
1.1.1.2. HbC
1.1.1.3. HbE
1.1.2. Quantitative : Thalassemia
1.1.2.1. Alpha thalassemia
1.1.2.2. Beta thalassemia
1.2. Acquired
1.2.1. MetHb (Fe2+ to Fe3+) --- unstable to bind oxygen --- hypoxia --- cyanosis
2. Treatment
2.1. fetal hemoglobin (HbF)
2.1.1. HbF inducers
2.1.1.1. hydroxyurea
2.1.1.1.1. Pharmocogenomics
2.1.1.1.2. erythroid regeneration
2.1.1.1.3. activate cGMP-dependent protein kinase
2.1.1.2. erythropoietin
2.1.1.2.1. erythroid regeneration
2.1.1.3. cisplatin
2.1.1.3.1. Most potent inducer
2.1.1.3.2. high toxicity
2.1.1.4. myleran
2.1.1.5. Short chain fatty acids
2.1.1.6. Combination of gene therapy
2.1.1.7. natural compounds
2.1.1.7.1. angelicin
2.1.1.7.2. linear psoralens
2.1.1.7.3. resveratrol
2.1.1.7.4. rapamycin
2.1.1.7.5. Mithramycin
2.1.1.7.6. ethanol extracts Fructus trichosanthis
2.1.1.8. Histone deacetylase (HDAC) inhibitor agents
2.1.1.8.1. Sodium butylate
2.1.1.8.2. butylate
2.1.1.8.3. 5-azacitidine
2.1.1.8.4. apicidin
2.1.1.8.5. Trichostatin
2.1.1.8.6. decitabine
2.1.1.8.7. hydroxamic acid derivatives
2.1.1.8.8. new immunomodulator drugs
2.1.1.9. synergistic effect of drug
2.1.1.9.1. efficient induction
2.1.1.9.2. different mechanisms of each drug
2.1.2. Mechanism
2.1.2.1. trigger several molecular signaling pathways (all signaling pathway are triggered by EPO)
2.1.2.1.1. JAK/STAT
2.1.2.1.2. MAPK(mitogen activated protein kinas)
2.1.2.1.3. Phosphoinositide 3-kinase(PI3K)
2.1.2.1.4. RAS
2.1.2.2. Molecular targets (regulating erythroid transcription factor and erythroid gene expression programs)
2.1.2.2.1. BCL11A
2.1.2.2.2. SOX6
2.1.2.2.3. KLF1
2.1.2.2.4. c-MYb
2.1.2.2.5. miRNAs 15a
2.1.2.2.6. miRNA 16-1
2.1.2.2.7. HDAC1
2.1.2.2.8. HDAC2
2.1.2.3. Chromatin modifiers
2.1.2.3.1. Histone deacetylase (HDAC) inhibitor agents
2.1.2.3.2. DNA binding
2.1.3. during fetal life for transport oxygen
2.1.4. Advantage of increase HbF
2.1.4.1. to prevent the beta-hemoglobinopathies
2.1.4.1.1. beta-thalassemia
2.1.4.1.2. HbE disease
2.1.4.1.3. sickle cell
2.1.4.1.4. Autosomal recessive inheritance
2.1.4.1.5. treatment
2.1.5. target for study
2.1.5.1. Chemical compound for induce HbF
2.1.5.1.1. mechanism action of these drugs
2.1.5.1.2. step for add drugs in Phase 2
2.1.5.2. genetic regulation of switch (HbA to HbF)
2.1.6. experiment
2.1.6.1. in vivo
2.1.6.1.1. mice
2.1.6.1.2. baboon
2.1.6.2. in vitro
2.1.6.2.1. cell culture