{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T08:02:19Z","timestamp":1767168139699,"version":"3.48.0"},"reference-count":70,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"vor","delay-in-days":29,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Red blood cells (RBCs) contain the highest purine nucleoside phosphorylase (PNP) level per cell volume, yet the role of PNP in the pathogenesis of sickle cell disease (SCD) is incompletely understood, highlighting an important gap in our knowledge of the disease. Previously, we reported increased PNP release by RBCs and accelerated purine nucleoside metabolism with increased production of pro\u2010oxidant, pro\u2010inflammatory and vasculotoxic byproducts in children with SCD and animal models of hemolytic injury. Thus, we hypothesized that PNP inhibition would reduce hemolysis and attenuate end\u2010organ damage in SCD. In adult patients with SCD (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200963), plasma PNP levels were markedly elevated compared to controls (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200927;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) and correlated positively with LDH (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u20090.6032,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) and negatively with haemoglobin (\n                    <jats:italic>r<\/jats:italic>\n                    \u2009=\u2009\u22120.4523,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0002). SCD mice also showed accelerated purine metabolism compared to controls. Treatment with the PNP inhibitor 8\u2010aminoguanosine (8\u2010AG) increased inosine and guanosine and reduced downstream vasculotoxic byproducts hypoxanthine (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.036), xanthine (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.004) and guanine (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.047), indicating efficient PNP inhibition. 8\u2010AG treatment rebalanced the purine metabolome in SCD mice to favour protective over harmful purine metabolites without negatively affecting haematological parameters. This was associated with reduced hemolysis and decreased splenomegaly, hepatomegaly, and hepatic and renal injury. This study suggests that PNP is an important erythrocytic damage\u2010associated molecular pattern molecule involved in the complex pathophysiology of SCD and proposes PNP inhibitors as a new therapeutic option for SCD and other hemolytic diseases.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.70996","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T04:21:15Z","timestamp":1767154875000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Purine Nucleoside Phosphorylase Inhibition Rebalances Purine Metabolism and Attenuates Organ Damage in Sickle Cell Mice"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0817-5027","authenticated-orcid":false,"given":"Adekunle Emmanuel","family":"Alagbe","sequence":"first","affiliation":[{"name":"Heart, Lung, Blood and Vascular Medicine Institute University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"},{"name":"Department of Medicine University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lynda","family":"Little\u2010Ihrig","sequence":"additional","affiliation":[{"name":"Heart, Lung, Blood and Vascular Medicine Institute University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"},{"name":"Department of Medicine University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie M.","family":"Mutchler","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"},{"name":"Division of Renal Electrolytes University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwin K.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrico M.","family":"Novelli","sequence":"additional","affiliation":[{"name":"Heart, Lung, Blood and Vascular Medicine Institute University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"},{"name":"Department of Medicine University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"},{"name":"Division of Classical Hematology University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7663-2723","authenticated-orcid":false,"given":"Stevan P.","family":"Tofovic","sequence":"additional","affiliation":[{"name":"Heart, Lung, Blood and Vascular Medicine Institute University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"},{"name":"Department of Medicine University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"},{"name":"Department of Pharmacology and Chemical Biology University of Pittsburgh School of Medicine  Pittsburgh Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_12_2_1","DOI":"10.1016\/S2352-3026(23)00118-7"},{"doi-asserted-by":"publisher","key":"e_1_2_12_3_1","DOI":"10.1038\/ncomms1104"},{"doi-asserted-by":"publisher","key":"e_1_2_12_4_1","DOI":"10.1182\/blood.V65.1.183.183"},{"doi-asserted-by":"publisher","key":"e_1_2_12_5_1","DOI":"10.1038\/178792a0"},{"doi-asserted-by":"publisher","key":"e_1_2_12_6_1","DOI":"10.1126\/science.110.2865.543"},{"doi-asserted-by":"publisher","key":"e_1_2_12_7_1","DOI":"10.1016\/S0950-3536(98)80074-7"},{"doi-asserted-by":"publisher","key":"e_1_2_12_8_1","DOI":"10.1146\/annurev-pathmechdis-012418-012838"},{"doi-asserted-by":"publisher","key":"e_1_2_12_9_1","DOI":"10.1111\/ejh.13430"},{"doi-asserted-by":"publisher","key":"e_1_2_12_10_1","DOI":"10.3324\/haematol.2012.068965"},{"doi-asserted-by":"publisher","key":"e_1_2_12_11_1","DOI":"10.3389\/fphys.2021.754638"},{"doi-asserted-by":"publisher","key":"e_1_2_12_12_1","DOI":"10.1134\/S0006297906050014"},{"doi-asserted-by":"publisher","key":"e_1_2_12_13_1","DOI":"10.1016\/S0163-7258(00)00097-8"},{"doi-asserted-by":"publisher","key":"e_1_2_12_14_1","DOI":"10.1177\/2045894018791557"},{"issue":"3","key":"e_1_2_12_15_1","first-page":"5","article-title":"Dimethyl Sulfoxide Induces Hemolysis and Pulmonary Hypertension","volume":"43","author":"Tofovic S. P.","year":"2022","journal-title":"Pril (Makedon Akad Nauk Umet Odd Med Nauki)"},{"doi-asserted-by":"publisher","key":"e_1_2_12_16_1","DOI":"10.1016\/j.mehy.2008.12.043"},{"doi-asserted-by":"publisher","key":"e_1_2_12_17_1","DOI":"10.1111\/j.1549-8719.2011.00158.x"},{"doi-asserted-by":"publisher","key":"e_1_2_12_18_1","DOI":"10.1373\/clinchem.2006.076364"},{"doi-asserted-by":"publisher","key":"e_1_2_12_19_1","DOI":"10.1172\/JCI114213"},{"doi-asserted-by":"publisher","key":"e_1_2_12_20_1","DOI":"10.1016\/j.bbrc.2016.11.119"},{"doi-asserted-by":"publisher","key":"e_1_2_12_21_1","DOI":"10.1021\/bi992170y"},{"doi-asserted-by":"publisher","key":"e_1_2_12_22_1","DOI":"10.1016\/j.bmc.2010.07.054"},{"doi-asserted-by":"publisher","key":"e_1_2_12_23_1","DOI":"10.2174\/0115734021277772240124075120"},{"doi-asserted-by":"publisher","key":"e_1_2_12_24_1","DOI":"10.3390\/molecules27144644"},{"doi-asserted-by":"publisher","key":"e_1_2_12_25_1","DOI":"10.1007\/s11302-015-9475-2"},{"doi-asserted-by":"publisher","key":"e_1_2_12_26_1","DOI":"10.1016\/j.neuint.2012.05.021"},{"doi-asserted-by":"publisher","key":"e_1_2_12_27_1","DOI":"10.1667\/RR3552.1"},{"doi-asserted-by":"publisher","key":"e_1_2_12_28_1","DOI":"10.1002\/jnr.23156"},{"doi-asserted-by":"publisher","key":"e_1_2_12_29_1","DOI":"10.1006\/jsre.2002.6519"},{"doi-asserted-by":"publisher","key":"e_1_2_12_30_1","DOI":"10.1161\/01.STR.0000155747.15679.04"},{"doi-asserted-by":"publisher","key":"e_1_2_12_31_1","DOI":"10.1016\/j.ejcts.2006.04.003"},{"doi-asserted-by":"publisher","key":"e_1_2_12_32_1","DOI":"10.4049\/jimmunol.164.2.1013"},{"doi-asserted-by":"publisher","key":"e_1_2_12_33_1","DOI":"10.1097\/00000658-200204000-00016"},{"doi-asserted-by":"publisher","key":"e_1_2_12_34_1","DOI":"10.1016\/j.ijcard.2017.08.006"},{"doi-asserted-by":"publisher","key":"e_1_2_12_35_1","DOI":"10.1161\/01.ATV.0000174798.25085.d6"},{"doi-asserted-by":"publisher","key":"e_1_2_12_36_1","DOI":"10.1124\/jpet.110.166058"},{"doi-asserted-by":"publisher","key":"e_1_2_12_37_1","DOI":"10.1007\/s12035-014-8815-5"},{"doi-asserted-by":"publisher","key":"e_1_2_12_38_1","DOI":"10.1111\/j.1476-5381.2009.00597.x"},{"doi-asserted-by":"publisher","key":"e_1_2_12_39_1","DOI":"10.1016\/j.jpain.2009.06.010"},{"doi-asserted-by":"publisher","key":"e_1_2_12_40_1","DOI":"10.1016\/j.mehy.2023.111045"},{"doi-asserted-by":"publisher","key":"e_1_2_12_41_1","DOI":"10.1371\/journal.pone.0160608"},{"doi-asserted-by":"publisher","key":"e_1_2_12_42_1","DOI":"10.1016\/j.trsl.2022.10.007"},{"doi-asserted-by":"publisher","key":"e_1_2_12_43_1","DOI":"10.3390\/ijms241310452"},{"doi-asserted-by":"publisher","key":"e_1_2_12_44_1","DOI":"10.1038\/s41598-022-22349-z"},{"doi-asserted-by":"publisher","key":"e_1_2_12_45_1","DOI":"10.1165\/rcmb.2017-0292OC"},{"doi-asserted-by":"publisher","key":"e_1_2_12_46_1","DOI":"10.1097\/FJC.0000000000000446"},{"doi-asserted-by":"publisher","key":"e_1_2_12_47_1","DOI":"10.1186\/s12947-020-00191-5"},{"doi-asserted-by":"publisher","key":"e_1_2_12_48_1","DOI":"10.1124\/jpet.117.243758"},{"doi-asserted-by":"publisher","key":"e_1_2_12_49_1","DOI":"10.1038\/s41598-024-73159-4"},{"doi-asserted-by":"publisher","key":"e_1_2_12_50_1","DOI":"10.1007\/s10875-023-01532-5"},{"doi-asserted-by":"publisher","key":"e_1_2_12_51_1","DOI":"10.1001\/jama.294.1.81"},{"doi-asserted-by":"publisher","key":"e_1_2_12_52_1","DOI":"10.1152\/ajplung.00302.2018"},{"doi-asserted-by":"publisher","key":"e_1_2_12_53_1","DOI":"10.1056\/NEJM199406093302303"},{"doi-asserted-by":"publisher","key":"e_1_2_12_54_1","DOI":"10.1111\/bjh.12690"},{"doi-asserted-by":"publisher","key":"e_1_2_12_55_1","DOI":"10.1053\/j.ackd.2022.03.004"},{"doi-asserted-by":"publisher","key":"e_1_2_12_56_1","DOI":"10.1111\/apt.13347"},{"doi-asserted-by":"publisher","key":"e_1_2_12_57_1","DOI":"10.1007\/BF01318115"},{"doi-asserted-by":"publisher","key":"e_1_2_12_58_1","DOI":"10.1016\/S0021-9258(19)39184-7"},{"doi-asserted-by":"publisher","key":"e_1_2_12_59_1","DOI":"10.1016\/0026-0495(76)90011-1"},{"doi-asserted-by":"publisher","key":"e_1_2_12_60_1","DOI":"10.1021\/bi00672a013"},{"doi-asserted-by":"publisher","key":"e_1_2_12_61_1","DOI":"10.1182\/blood-2024-199595"},{"issue":"5","key":"e_1_2_12_62_1","first-page":"III224","article-title":"Myocardial Reperfusion Injury. Role of Myocardial Hypoxanthine and Xanthine in Free Radical\u2010Mediated Reperfusion Injury","volume":"78","author":"Abd\u2010Elfattah A. S.","year":"1988","journal-title":"Circulation"},{"doi-asserted-by":"publisher","key":"e_1_2_12_63_1","DOI":"10.1161\/ATVBAHA.120.315081"},{"doi-asserted-by":"publisher","key":"e_1_2_12_64_1","DOI":"10.1007\/978-1-4684-5104-7_96"},{"doi-asserted-by":"publisher","key":"e_1_2_12_65_1","DOI":"10.1056\/NEJM197703242961203"},{"doi-asserted-by":"publisher","key":"e_1_2_12_66_1","DOI":"10.1007\/s004390050787"},{"doi-asserted-by":"publisher","key":"e_1_2_12_67_1","DOI":"10.3389\/fimmu.2020.01257"},{"doi-asserted-by":"publisher","key":"e_1_2_12_68_1","DOI":"10.1172\/jci.insight.140109"},{"key":"e_1_2_12_69_1","article-title":"Inhibition of Purine Nucleoside Phosphorylase Retards the Progression of Angioproliferative Pulmonary Hypertension in Female Rats","volume":"197","author":"Tofovic S. P. H.","year":"2018","journal-title":"American Journal of Respiratory and Critical Care Medicine"},{"key":"e_1_2_12_70_1","article-title":"Purine Nucleoside Phosphorylase Inhibition Attenuates the Metabolic Syndrome and Associated Pulmonary Hypertension and Right Ventricular Dysfunction","volume":"199","author":"Tofovic S. P. H.","year":"2019","journal-title":"American Journal of Respiratory and Critical Care Medicine"},{"key":"e_1_2_12_71_1","first-page":"35","volume-title":"Developments in Cancer Chemotherapy","author":"Stoeckler J. D.","year":"1984"}],"container-title":["Journal of Cellular and Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jcmm.70996","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T07:58:33Z","timestamp":1767167913000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jcmm.70996"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":70,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1111\/jcmm.70996"],"URL":"https:\/\/doi.org\/10.1111\/jcmm.70996","archive":["Portico"],"relation":{},"ISSN":["1582-1838","1582-4934"],"issn-type":[{"type":"print","value":"1582-1838"},{"type":"electronic","value":"1582-4934"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-07-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70996"}}