International Journal of Molecular Medical Science, 2024, Vol.14, No.4, 203-215 http://medscipublisher.com/index.php/ijmms 205 the central event in the molecular pathogenesis of SCA, leading to the characteristic clinical manifestations of the disease. Figure 1 The Promoting Effect of NRF2 on the Expression of DNMT1 and DNMT3b (Adapted from Silva-Llanes et al., 2023) Image caption: A: qPCR was used to measure the mRNA levels of Dnmt1, Dnmt3a, and Dnmt3b in Nfe2l2+/+ and Nfe2l2−/ − mouse embryonic fibroblasts (MEFs); B: Western blot analysis was conducted to assess the protein levels of DNMT1, DNMT3a, and DNMT3b in the same samples, followed by densitometric quantification; C: Time-course analysis of the changes in mRNA levels of Dnmt1, Dnmt3a, and Dnmt3b in hippocampal HT22 cells after DMF treatment; D: Western blot analysis of the corresponding DNMT1, DNMT3a, and DNMT3b protein levels, with densitometric quantification (Adapted from Silva-Llanes et al., 2023) 3.2 Pathophysiology of SCA The pathophysiology of SCA is complex and multifaceted. The sickling of red blood cells results in chronic hemolysis and vaso-occlusion, which in turn lead to ischemia-reperfusion injury, endothelial dysfunction, and chronic inflammation. These processes contribute to the wide range of complications seen in SCA, including pain crises, organ damage, and increased risk of infections. Oxidative stress plays a significant role in the pathophysiology, as sickled cells are more prone to oxidative damage, which exacerbates hemolysis and inflammation (Figure 2) (Sangokoya et al., 2010; Silva and Faustino, 2023). Additionally, the disease is phenotypically heterogeneous, influenced by both genetic and environmental factors, which modulate the severity and presentation of symptoms (Steinberg and Sebastiani, 2012; Silva and Faustino, 2023). Silva and Faustino (2023) investigated the mechanisms of oxidative stress in sickle cell disease, illustrating the pathological processes from the formation of sickled red blood cells to vascular occlusion and ultimately organ
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