International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 206 ischemia. Figure 2 reveals how HbS induces membrane damage and hemolysis, leading to nitric oxide (NO) depletion and oxidative stress, which in turn causes vascular dysfunction and thrombosis, resulting in ischemic injury. By elucidating this mechanism, the study emphasizes the potential of targeting oxidative stress and related molecular pathways in treating SCD to slow disease progression and reduce the risk of complications. Figure 2 Pathways of Oxidative Stress Mechanisms in Sickle Cell Disease (Adapted from Silva and Faustino, 2023) Image caption: The image illustrates the central role of oxidative stress in the progression of Sickle Cell Disease (SCD). In low-oxygen conditions, hemoglobin S (HbS) in sickle-shaped red blood cells (SSRBCs) polymerizes, leading to the formation of sickle cells, membrane damage, and hemolysis. The released Hb further reduces nitric oxide (NO) levels, promoting vasoconstriction and endothelial cell activation, which leads to vascular occlusion (thrombosis). Vascular occlusion and hypoxia ultimately result in ischemia and organ damage, particularly triggering ischemic strokes in the brain (Adapted from Silva and Faustino, 2023). 3.3 Current genetic understanding Recent advances in genetic research have provided deeper insights into the genetic modifiers and regulatory mechanisms that influence the severity of SCA. One of the key genetic factors is the concentration of fetal hemoglobin (HbF), which can ameliorate the severity of SCA by inhibiting HbS polymerization. Genetic variants that delay the switch from fetal to adult hemoglobin, such as those affecting the BCL11A gene, have been identified as potential therapeutic targets (Chen et al., 2017; Williams and Thein, 2018). Additionally, the presence of co-inherited α-thalassemia can modulate the clinical phenotype of SCA by reducing the overall hemoglobin concentration and thereby decreasing the likelihood of vaso-occlusion (Steinberg and Sebastiani, 2012). Epigenetic factors, such as DNA methylation and histone modifications, also play a crucial role in the regulation of gene expression in SCA, influencing the disease's progression and response to treatment (Wang et al., 2020; Bao et al., 2021; Lê et al., 2023). These genetic and epigenetic insights are paving the way for novel therapeutic approaches, including gene therapy and targeted drug development, aimed at reactivating HbF production and correcting the underlying genetic defect (Williams and Thein, 2018; Wang et al., 2020; Bao et al., 2021). 4 Epigenetic Modulation of Fetal Hemoglobin (HbF) in Sickle Cell Anemia 4.1 Role of HbF in ameliorating SCA symptoms Fetal hemoglobin (HbF) plays a crucial role in mitigating the symptoms of sickle cell anemia (SCA). HbF can inhibit the polymerization of deoxyhemoglobin S (HbS), which is responsible for the sickling of red blood cells. This inhibition helps to reduce the vaso-occlusive crises and hemolytic anemia that characterize SCA (Bae et al., 2012; Steinberg, 2020). The protective effect of HbF is evident in patients with higher HbF levels, who generally exhibit milder disease phenotypes. For instance, individuals with the Senegal and Saudi-Indian haplotypes, which are associated with higher HbF levels, tend to have less severe clinical manifestations of SCA (Akinsheye et al., 2011).
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