Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria : association with disease severity

Decreased bioavailability of nitric oxide (NO) is a major contributor to the pathophysiology of severe falciparum malaria. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthesis from L-arginine. We hypothesized that systemic levels of BH4 would be decreased in children with cerebr...

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Main Authors: Granger, Donald L., Rubach, Matthew P., Mukemba, Jackson, Florence, Salvatore, Lopansri, Bert K., Hyland, Keith, Volkheimer, Alicia D., Yeo, Tsin W., Anstey, Nicholas M., Weinberg, J. Brice, Mwaikambo, Esther D.
Other Authors: Kim, Kami
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Language:English
Published: 2015
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Online Access:https://hdl.handle.net/10356/107301
http://hdl.handle.net/10220/25537
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spelling sg-ntu-dr.10356-1073012022-02-16T16:30:41Z Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria : association with disease severity Granger, Donald L. Rubach, Matthew P. Mukemba, Jackson Florence, Salvatore Lopansri, Bert K. Hyland, Keith Volkheimer, Alicia D. Yeo, Tsin W. Anstey, Nicholas M. Weinberg, J. Brice Mwaikambo, Esther D. Kim, Kami Lee Kong Chian School of Medicine (LKCMedicine) DRNTU::Science::Medicine Decreased bioavailability of nitric oxide (NO) is a major contributor to the pathophysiology of severe falciparum malaria. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthesis from L-arginine. We hypothesized that systemic levels of BH4 would be decreased in children with cerebral malaria, contributing to low NO bioavailability. In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states (fully reduced [BH4] and the oxidized metabolites, dihydrobiopterin [BH2] and biopterin [B0]) in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 45), non-malaria central nervous system conditions (NMC, n = 48), and in 111 healthy controls (HC). Median urine BH4 concentration in CM (1.10 [IQR:0.55–2.18] μmol/mmol creatinine) was significantly lower compared to each of the other three groups — UM (2.10 [IQR:1.32–3.14];p<0.001), NMC (1.52 [IQR:1.01–2.71];p = 0.002), and HC (1.60 [IQR:1.15–2.23];p = 0.005). Oxidized biopterins were increased, and the BH4:BH2 ratio markedly decreased in CM. In a multivariate logistic regression model, each Log10-unit decrease in urine BH4 was independently associated with a 3.85-fold (95% CI:1.89–7.61) increase in odds of CM (p<0.001). Low systemic BH4 levels and increased oxidized biopterins contribute to the low NO bioavailability observed in CM. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria. Published version 2015-05-14T04:32:39Z 2019-12-06T22:28:26Z 2015-05-14T04:32:39Z 2019-12-06T22:28:26Z 2015 2015 Journal Article Rubach, M. P., Mukemba, J., Florence, S., Lopansri, B. K., Hyland, K., Volkheimer, A. D., et al. (2015). Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria : association with disease severity. PLOS pathogens, 11(3), e1004655-. 1553-7374 https://hdl.handle.net/10356/107301 http://hdl.handle.net/10220/25537 10.1371/journal.ppat.1004655 25764173 en PLOS pathogens This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. 22 p. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic DRNTU::Science::Medicine
spellingShingle DRNTU::Science::Medicine
Granger, Donald L.
Rubach, Matthew P.
Mukemba, Jackson
Florence, Salvatore
Lopansri, Bert K.
Hyland, Keith
Volkheimer, Alicia D.
Yeo, Tsin W.
Anstey, Nicholas M.
Weinberg, J. Brice
Mwaikambo, Esther D.
Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria : association with disease severity
description Decreased bioavailability of nitric oxide (NO) is a major contributor to the pathophysiology of severe falciparum malaria. Tetrahydrobiopterin (BH4) is an enzyme cofactor required for NO synthesis from L-arginine. We hypothesized that systemic levels of BH4 would be decreased in children with cerebral malaria, contributing to low NO bioavailability. In an observational study in Tanzania, we measured urine levels of biopterin in its various redox states (fully reduced [BH4] and the oxidized metabolites, dihydrobiopterin [BH2] and biopterin [B0]) in children with uncomplicated malaria (UM, n = 55), cerebral malaria (CM, n = 45), non-malaria central nervous system conditions (NMC, n = 48), and in 111 healthy controls (HC). Median urine BH4 concentration in CM (1.10 [IQR:0.55–2.18] μmol/mmol creatinine) was significantly lower compared to each of the other three groups — UM (2.10 [IQR:1.32–3.14];p<0.001), NMC (1.52 [IQR:1.01–2.71];p = 0.002), and HC (1.60 [IQR:1.15–2.23];p = 0.005). Oxidized biopterins were increased, and the BH4:BH2 ratio markedly decreased in CM. In a multivariate logistic regression model, each Log10-unit decrease in urine BH4 was independently associated with a 3.85-fold (95% CI:1.89–7.61) increase in odds of CM (p<0.001). Low systemic BH4 levels and increased oxidized biopterins contribute to the low NO bioavailability observed in CM. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.
author2 Kim, Kami
author_facet Kim, Kami
Granger, Donald L.
Rubach, Matthew P.
Mukemba, Jackson
Florence, Salvatore
Lopansri, Bert K.
Hyland, Keith
Volkheimer, Alicia D.
Yeo, Tsin W.
Anstey, Nicholas M.
Weinberg, J. Brice
Mwaikambo, Esther D.
format Article
author Granger, Donald L.
Rubach, Matthew P.
Mukemba, Jackson
Florence, Salvatore
Lopansri, Bert K.
Hyland, Keith
Volkheimer, Alicia D.
Yeo, Tsin W.
Anstey, Nicholas M.
Weinberg, J. Brice
Mwaikambo, Esther D.
author_sort Granger, Donald L.
title Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria : association with disease severity
title_short Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria : association with disease severity
title_full Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria : association with disease severity
title_fullStr Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria : association with disease severity
title_full_unstemmed Impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria : association with disease severity
title_sort impaired systemic tetrahydrobiopterin bioavailability and increased oxidized biopterins in pediatric falciparum malaria : association with disease severity
publishDate 2015
url https://hdl.handle.net/10356/107301
http://hdl.handle.net/10220/25537
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