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HIF-PHD inhibitor desidustat ameliorates iron deficiency anemia
Iron deficiency anemia is caused by many pathological conditions like chronic kidney disease (CKD), inflammation, malnutrition and gastrointestinal abnormality. Current treatments that are erythropoiesis stimulating agents (ESAs) and iron supplementation are inadequate and often lead to tolerance an...
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Published in: | Toxicology and applied pharmacology 2024-02, Vol.483, p.116832-116832, Article 116832 |
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creator | Patel, Vishal J. Joharapurkar, Amit Kshirsagar, Samadhan G. Patel, Maulik S. Savsani, Hardikkumar H. Dodiya, Harshad S. Rakhasiya, Milan H. Kajavadara, Chetan Valani, Darshan Jain, Mukul R. |
description | Iron deficiency anemia is caused by many pathological conditions like chronic kidney disease (CKD), inflammation, malnutrition and gastrointestinal abnormality. Current treatments that are erythropoiesis stimulating agents (ESAs) and iron supplementation are inadequate and often lead to tolerance and/or toxicity. Desidustat, a prolyl hydroxylase (PHD) inhibitor, is clinically used for the treatment of anemia with CKD. In this study, we investigated the effect of desidustat on iron deficiency anemia (IDA). IDA was induced in C57BL6/J mice by iron deficient diet feeding. These mice were then treated with desidustat (15 mg/kg, PO) and FeSO4 (20 mg/kg) for five weeks and effect of the treatment on hematology, iron homeostasis, and bone marrow histology was observed. Effect of desidustat on iron metabolism in inflammation (LPS)-induced iron deficiency was also assessed. Both, Desidustat and FeSO4, increased MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), hemoglobin, and HCT (hematocrit) in blood and increased iron in serum, liver, and spleen. Desidustat increased MCHC (mean corpuscular hemoglobin concentration) while FeSO4 treatment did not alter it. FeSO4 treatment significantly increased iron deposition in liver, and spleen, while desidustat increased iron in circulation and demonstrated efficient iron utilization. Desidustat increased iron absorption, serum iron and decreased hepcidin without altering tissue iron, while FeSO4 increased serum and tissue iron by increasing hepcidin in LPS-induced iron deficiency. Desidustat increased erythroid population, especially iron-dependent polychromatic normoblasts and orthochromatic normoblasts, while FeSO4 did not improve cell architecture. PHD inhibition by desidustat improved iron utilization in iron deficiency anemia, by efficient erythropoiesis.
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•Prolyl hydroxylase inhibitor desidustat increases Hb and MCV in iron deficiency anemia.•Desidustat increased iron in serum and tissue stores without iron supplementation.•Prolyl hydroxylase inhibition increased iron absorption.•Desidustat increased erythroid cells and their maturation in bone marrow.•It also prevented localization of iron in tissue induced by LPS. |
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[Display omitted]
•Prolyl hydroxylase inhibitor desidustat increases Hb and MCV in iron deficiency anemia.•Desidustat increased iron in serum and tissue stores without iron supplementation.•Prolyl hydroxylase inhibition increased iron absorption.•Desidustat increased erythroid cells and their maturation in bone marrow.•It also prevented localization of iron in tissue induced by LPS.</description><identifier>ISSN: 0041-008X</identifier><identifier>EISSN: 1096-0333</identifier><identifier>DOI: 10.1016/j.taap.2024.116832</identifier><identifier>PMID: 38266872</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Iron deficiency anemia ; Prolyl hydroxylase inhibitor</subject><ispartof>Toxicology and applied pharmacology, 2024-02, Vol.483, p.116832-116832, Article 116832</ispartof><rights>2024 Elsevier Inc.</rights><rights>Copyright © 2024 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-3f581bd9f91e6b3fae090ae710835d62ff7b407faf53baf8b4f21d263e3082fc3</citedby><cites>FETCH-LOGICAL-c356t-3f581bd9f91e6b3fae090ae710835d62ff7b407faf53baf8b4f21d263e3082fc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38266872$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Patel, Vishal J.</creatorcontrib><creatorcontrib>Joharapurkar, Amit</creatorcontrib><creatorcontrib>Kshirsagar, Samadhan G.</creatorcontrib><creatorcontrib>Patel, Maulik S.</creatorcontrib><creatorcontrib>Savsani, Hardikkumar H.</creatorcontrib><creatorcontrib>Dodiya, Harshad S.</creatorcontrib><creatorcontrib>Rakhasiya, Milan H.</creatorcontrib><creatorcontrib>Kajavadara, Chetan</creatorcontrib><creatorcontrib>Valani, Darshan</creatorcontrib><creatorcontrib>Jain, Mukul R.</creatorcontrib><title>HIF-PHD inhibitor desidustat ameliorates iron deficiency anemia</title><title>Toxicology and applied pharmacology</title><addtitle>Toxicol Appl Pharmacol</addtitle><description>Iron deficiency anemia is caused by many pathological conditions like chronic kidney disease (CKD), inflammation, malnutrition and gastrointestinal abnormality. Current treatments that are erythropoiesis stimulating agents (ESAs) and iron supplementation are inadequate and often lead to tolerance and/or toxicity. Desidustat, a prolyl hydroxylase (PHD) inhibitor, is clinically used for the treatment of anemia with CKD. In this study, we investigated the effect of desidustat on iron deficiency anemia (IDA). IDA was induced in C57BL6/J mice by iron deficient diet feeding. These mice were then treated with desidustat (15 mg/kg, PO) and FeSO4 (20 mg/kg) for five weeks and effect of the treatment on hematology, iron homeostasis, and bone marrow histology was observed. Effect of desidustat on iron metabolism in inflammation (LPS)-induced iron deficiency was also assessed. Both, Desidustat and FeSO4, increased MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), hemoglobin, and HCT (hematocrit) in blood and increased iron in serum, liver, and spleen. Desidustat increased MCHC (mean corpuscular hemoglobin concentration) while FeSO4 treatment did not alter it. FeSO4 treatment significantly increased iron deposition in liver, and spleen, while desidustat increased iron in circulation and demonstrated efficient iron utilization. Desidustat increased iron absorption, serum iron and decreased hepcidin without altering tissue iron, while FeSO4 increased serum and tissue iron by increasing hepcidin in LPS-induced iron deficiency. Desidustat increased erythroid population, especially iron-dependent polychromatic normoblasts and orthochromatic normoblasts, while FeSO4 did not improve cell architecture. PHD inhibition by desidustat improved iron utilization in iron deficiency anemia, by efficient erythropoiesis.
[Display omitted]
•Prolyl hydroxylase inhibitor desidustat increases Hb and MCV in iron deficiency anemia.•Desidustat increased iron in serum and tissue stores without iron supplementation.•Prolyl hydroxylase inhibition increased iron absorption.•Desidustat increased erythroid cells and their maturation in bone marrow.•It also prevented localization of iron in tissue induced by LPS.</description><subject>Iron deficiency anemia</subject><subject>Prolyl hydroxylase inhibitor</subject><issn>0041-008X</issn><issn>1096-0333</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp9kMFKw0AQhhdRbK2-gAfJ0UvqzG6y2YAgUq0tFPSg4G3ZJLO4JWnqbir07U1t9ehpDvP9PzMfY5cIYwSUN8txZ8x6zIEnY0SpBD9iQ4RcxiCEOGZDgARjAPU-YGchLAEgTxI8ZQOhuJQq40N2N5tP45fZQ-RWH65wXeujioKrNqEzXWQaql3rTUchcr5d9TvrSkerchuZFTXOnLMTa-pAF4c5Ym_Tx9fJLF48P80n94u4FKnsYmFThUWV2xxJFsIaghwMZQhKpJXk1mZFApk1NhWFsapILMeKS0ECFLelGLHrfe_at58bCp1uXCiprvsz2k3QPEeVYiIRe5Tv0dK3IXiyeu1dY_xWI-idOL3UO3F6J07vxfWhq0P_pmio-ov8muqB2z1A_ZdfjrwOPyKocp7KTlet-6__G5dufnA</recordid><startdate>202402</startdate><enddate>202402</enddate><creator>Patel, Vishal J.</creator><creator>Joharapurkar, Amit</creator><creator>Kshirsagar, Samadhan G.</creator><creator>Patel, Maulik S.</creator><creator>Savsani, Hardikkumar H.</creator><creator>Dodiya, Harshad S.</creator><creator>Rakhasiya, Milan H.</creator><creator>Kajavadara, Chetan</creator><creator>Valani, Darshan</creator><creator>Jain, Mukul R.</creator><general>Elsevier Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202402</creationdate><title>HIF-PHD inhibitor desidustat ameliorates iron deficiency anemia</title><author>Patel, Vishal J. ; Joharapurkar, Amit ; Kshirsagar, Samadhan G. ; Patel, Maulik S. ; Savsani, Hardikkumar H. ; Dodiya, Harshad S. ; Rakhasiya, Milan H. ; Kajavadara, Chetan ; Valani, Darshan ; Jain, Mukul R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-3f581bd9f91e6b3fae090ae710835d62ff7b407faf53baf8b4f21d263e3082fc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Iron deficiency anemia</topic><topic>Prolyl hydroxylase inhibitor</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Patel, Vishal J.</creatorcontrib><creatorcontrib>Joharapurkar, Amit</creatorcontrib><creatorcontrib>Kshirsagar, Samadhan G.</creatorcontrib><creatorcontrib>Patel, Maulik S.</creatorcontrib><creatorcontrib>Savsani, Hardikkumar H.</creatorcontrib><creatorcontrib>Dodiya, Harshad S.</creatorcontrib><creatorcontrib>Rakhasiya, Milan H.</creatorcontrib><creatorcontrib>Kajavadara, Chetan</creatorcontrib><creatorcontrib>Valani, Darshan</creatorcontrib><creatorcontrib>Jain, Mukul R.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Toxicology and applied pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Patel, Vishal J.</au><au>Joharapurkar, Amit</au><au>Kshirsagar, Samadhan G.</au><au>Patel, Maulik S.</au><au>Savsani, Hardikkumar H.</au><au>Dodiya, Harshad S.</au><au>Rakhasiya, Milan H.</au><au>Kajavadara, Chetan</au><au>Valani, Darshan</au><au>Jain, Mukul R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HIF-PHD inhibitor desidustat ameliorates iron deficiency anemia</atitle><jtitle>Toxicology and applied pharmacology</jtitle><addtitle>Toxicol Appl Pharmacol</addtitle><date>2024-02</date><risdate>2024</risdate><volume>483</volume><spage>116832</spage><epage>116832</epage><pages>116832-116832</pages><artnum>116832</artnum><issn>0041-008X</issn><eissn>1096-0333</eissn><abstract>Iron deficiency anemia is caused by many pathological conditions like chronic kidney disease (CKD), inflammation, malnutrition and gastrointestinal abnormality. Current treatments that are erythropoiesis stimulating agents (ESAs) and iron supplementation are inadequate and often lead to tolerance and/or toxicity. Desidustat, a prolyl hydroxylase (PHD) inhibitor, is clinically used for the treatment of anemia with CKD. In this study, we investigated the effect of desidustat on iron deficiency anemia (IDA). IDA was induced in C57BL6/J mice by iron deficient diet feeding. These mice were then treated with desidustat (15 mg/kg, PO) and FeSO4 (20 mg/kg) for five weeks and effect of the treatment on hematology, iron homeostasis, and bone marrow histology was observed. Effect of desidustat on iron metabolism in inflammation (LPS)-induced iron deficiency was also assessed. Both, Desidustat and FeSO4, increased MCV (mean corpuscular volume), MCH (mean corpuscular hemoglobin), hemoglobin, and HCT (hematocrit) in blood and increased iron in serum, liver, and spleen. Desidustat increased MCHC (mean corpuscular hemoglobin concentration) while FeSO4 treatment did not alter it. FeSO4 treatment significantly increased iron deposition in liver, and spleen, while desidustat increased iron in circulation and demonstrated efficient iron utilization. Desidustat increased iron absorption, serum iron and decreased hepcidin without altering tissue iron, while FeSO4 increased serum and tissue iron by increasing hepcidin in LPS-induced iron deficiency. Desidustat increased erythroid population, especially iron-dependent polychromatic normoblasts and orthochromatic normoblasts, while FeSO4 did not improve cell architecture. PHD inhibition by desidustat improved iron utilization in iron deficiency anemia, by efficient erythropoiesis.
[Display omitted]
•Prolyl hydroxylase inhibitor desidustat increases Hb and MCV in iron deficiency anemia.•Desidustat increased iron in serum and tissue stores without iron supplementation.•Prolyl hydroxylase inhibition increased iron absorption.•Desidustat increased erythroid cells and their maturation in bone marrow.•It also prevented localization of iron in tissue induced by LPS.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>38266872</pmid><doi>10.1016/j.taap.2024.116832</doi><tpages>1</tpages></addata></record> |
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title | HIF-PHD inhibitor desidustat ameliorates iron deficiency anemia |
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