title: HbE/β-Thalassemia and Oxidative Stress: The Key to Pathophysiological Mechanisms and Novel Therapeutics.
abstract: Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The βE-globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected.
  
  
  
  While HbE by itself presents as a mild anemia and a single gene for β-thalassemia is not serious, it remains unexplained why HbE/β-thalassemia (HbE/β-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/β-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess α-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events.
  
  
  
  Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26, 794-813.
authors.affiliation: 1 Department of Medicine (Hematology), Albert Einstein College of Medicine , Bronx, New York.|2 Department of Anatomy and Structural Biology, Albert Einstein College of Medicine , Bronx, New York.
authors.forename: Rhoda Elison
authors.initials: RE
authors.lastname: Hirsch
authors.affiliation: 3 Department of Pharmacology, Faculty of Science, Mahidol University , Bangkok, Thailand .
authors.forename: Nathawut
authors.initials: N
authors.lastname: Sibmooh
authors.affiliation: 4 Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University , Nakornpathom, Thailand .
authors.forename: Suthat
authors.initials: S
authors.lastname: Fucharoen
authors.affiliation: 5 Department of Physiology and Biophysics, Albert Einstein College of Medicine , Bronx, New York.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D000818:Animals; D006446:Hemoglobin E / Q000235:genetics / Q000378:metabolism*; D006453:Hemoglobinopathies / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D018384:Oxidative Stress; D017354:Point Mutation; D017086:beta-Thalassemia / Q000235:genetics / Q000378:metabolism*
chemical_list: D006446:Hemoglobin E
keywords: hemoglobin E; hypoxia; inflammation; nitric oxide; oxidative stress; β-thalassemia