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DOI: 10.1101/2023.05.17.23290113

Sickle cell patients showed dysregulated plasma Rb/K ratio and Gamma-glutamyl cycle in red blood cells

S.Bhatt A. K. Mohapatra S. Meher ...+3 S. Kundu
Patients suffering from Sickle cell disease (SCD) present with multifactorial pathology, and a detailed understanding of it may help to develop novel therapeutics. In this study, the plasma elemental (24Mg, 44Ca, 57Fe, 63Cu, 66Zn, 77Se, 85Rb, 208Pb, and 39K) levels of SCD patients (n=10, male: 50%) and control groups (trait and healthy; n=10 each; male: 50%) were profiled using inductively coupled plasma mass spectrometry (ICP-MS). Additionally, comparative global erythrocyte metabolomics of SCD (n=5, male:100%) and healthy controls (n=5, male:100%) were carried out using liquid chromatography-mass spectrometry (LC-MS). SCD patients had higher plasma 24Mg, 44Ca, 66Zn, 208Pb, and 39K levels and lower levels of 57Fe, 77Se, and 85Rb compared to controls. These changes in elemental levels with a decreased Rb/K ratio, may explain the observed frequent hemolysis and severe dehydration with oxidative stress in the SCD group. Mass spectrometry analysis of RBCs (red blood cells) of SCD (n=5) and healthy controls (n=5) identified 442 unique metabolic features which separately clustered both the study groups in principal component analysis (PCA). A set of 136 features showed differential (p<0.05; log2fold change>+1 or -1) regulation and was involved in D-Glutamine/D-glutamate, Sphingolipid, Arginine biosynthesis, Glutathione and Glycine, serine and threonine metabolism. Interestingly, higher pyroglutamic acid levels were observed in the SS-RBCs (sickle shaped-RBC) indicating a perturbed gamma-glutamyl pathway in SCD patients. Supplementation of the depleted trace metals and targeting the perturbed metabolic pathways in the RBCs of SCD patients provides avenues for alternate therapeutics development.