{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T23:00:59Z","timestamp":1778886059239,"version":"3.51.4"},"reference-count":89,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,7,18]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>\n              In sickle cell disease (SCD), erythrocyte reactive oxygen species (ROS) production and oxidative stress play a critical role in vaso-occlusion, a hallmark of SCD. Small noncoding nucleolar RNAs (snoRNAs) of the\n              <jats:italic toggle=\"yes\">Rpl13a<\/jats:italic>\n              locus have been described as regulators of ROS levels. However, whether\n              <jats:italic toggle=\"yes\">Rpl13a<\/jats:italic>\n              snoRNAs are present in sickle red blood cells (RBCs) and regulate ROS levels and whether they contribute to SCD pathophysiology remain unknown.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              To determine whether sickle RBC ROS levels are associated with\n              <jats:italic toggle=\"yes\">Rpl13a<\/jats:italic>\n              snoRNA levels and identify the mechanism by which they regulate ROS and snoRNAs\u2019 effects on SCD hemodynamics, we used human RBCs,\n              <jats:italic toggle=\"yes\">Rpl13a<\/jats:italic>\n              snoRNA knockout sickle mice, K562\n              <jats:italic toggle=\"yes\">U32a<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">U33<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">U34<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">U35a<\/jats:italic>\n              , and the control\n              <jats:italic toggle=\"yes\">U25<\/jats:italic>\n              knockout mutants generated by CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats\/Cas9 protein)\u2013targeted genome editing, and genetic targeting with antisense oligonucleotides.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              Excessive ROS production in sickle RBCs of patients with SCD is associated with high\n              <jats:italic toggle=\"yes\">Rpl13a<\/jats:italic>\n              snoRNAs\n              <jats:italic toggle=\"yes\">U32a<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">U33<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">U34<\/jats:italic>\n              , and\n              <jats:italic toggle=\"yes\">U35a<\/jats:italic>\n              levels.\n              <jats:italic toggle=\"yes\">U32a<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">U34<\/jats:italic>\n              , and\n              <jats:italic toggle=\"yes\">U35a<\/jats:italic>\n              regulate ROS and hydrogen peroxide levels in sickle erythroid populations by modulating peroxidase activity. This was due to\n              <jats:italic toggle=\"yes\">U32a<\/jats:italic>\n              - and\n              <jats:italic toggle=\"yes\">U34<\/jats:italic>\n              -guided 2\u2019-O-methylation on\n              <jats:italic toggle=\"yes\">Prdx2<\/jats:italic>\n              (peroxiredoxin 2) messenger RNA, a modification conveyed by fibrillarin during erythropoiesis, subsequently reducing Prdx2 expression and activity. The snoRNA\n              <jats:italic toggle=\"yes\">U35a<\/jats:italic>\n              impaired Prdx2 expression\/activity but independently of\n              <jats:italic toggle=\"yes\">Prdx2<\/jats:italic>\n              messenger RNA 2\u2019-O-methylation. Excess sickle RBC ROS increased in turn\n              <jats:italic toggle=\"yes\">Rpl13a<\/jats:italic>\n              snoRNAs levels. In vivo targeting combinations of\n              <jats:italic toggle=\"yes\">U34<\/jats:italic>\n              +\n              <jats:italic toggle=\"yes\">U35a<\/jats:italic>\n              and\n              <jats:italic toggle=\"yes\">U32a<\/jats:italic>\n              +\n              <jats:italic toggle=\"yes\">U34<\/jats:italic>\n              +\n              <jats:italic toggle=\"yes\">U35a<\/jats:italic>\n              in sickle mice with antisense oligonucleotide blunted RBC ROS generation, improved erythropoiesis and anemia, alleviated leukocytosis and endothelial damage, diminished cell adhesion in inflamed vessels and vaso-occlusion, restored blood flow, and reduced animal mortality.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>\n              <jats:italic toggle=\"yes\">Rpl13a<\/jats:italic>\n              snoRNAs\n              <jats:italic toggle=\"yes\">U34<\/jats:italic>\n              and\n              <jats:italic toggle=\"yes\">U35a<\/jats:italic>\n              specifically increase ROS levels, which, in turn, regulate snoRNA expression, in sickle erythroid cells, modulating Prdx2 expression\/activity, subsequently impairing hemodynamics. Targeted U34+\n              <jats:italic toggle=\"yes\">U35a<\/jats:italic>\n              with antisense oligonucleotide may represent a novel and safe therapy to ameliorate erythropoiesis and downstream events in SCD.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.124.325093","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T05:00:12Z","timestamp":1747285212000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["<i>Rpl13a<\/i>\n            snoRNAs\n            <i>U34<\/i>\n            and\n            <i>U35a<\/i>\n            : New Targets for Sickle Cell Disease Complications"],"prefix":"10.1161","volume":"137","author":[{"given":"Waseem","family":"Chauhan","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, 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