Use of Peroxisome Proliferator‐Activated Receptor γ Agonists as Adjunctive Treatment for<i>Plasmodium falciparum</i>Malaria: A Randomized, Double‐Blind, Placebo‐Controlled Trial

Boggild, Andrea K.; Krudsood, Srivicha; Patel, Samir N.; Serghides, Lena; Tangpukdee, Noppadon; Katz, Kevin; Wilairatana, Polrat; Liles, W. Conrad; Looareesuwan, Sornchai; Kain, Kevin C.

doi:10.1086/605431

Cited by 70 publications

(65 citation statements)

References 36 publications

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“…In particular, enhanced PPARγ activity has been shown to increase CD36-mediated phagocytosis of P. falciparum-infected RBCs and the PPARγ agonist rosiglitazone was shown to enhance parasite clearance and reduce inflammation biomarkers in a human trial. [51][52][53] The reduction in leukocyte adherence in the liver with ABA treatment ( Figure 2B) corresponds with increased PPARγ transcript levels (Figure 3), which supports the use of PPARγ agonists as adjunctive treatments for severe malaria. 54 By extension, ABA supplementation, through these beneficial effects on PPARγ, could be used to ameliorate symptoms of severe or complicated malaria.…”

Section: Discussionsupporting

confidence: 55%

Supplementation with Abscisic Acid Reduces Malaria Disease Severity and Parasite Transmission

Glennon¹,

Adams²,

Hicks³

et al. 2016

The American Journal of Tropical Medicine and Hygiene

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Abstract. Nearly half of the world's population is at risk for malaria. Increasing drug resistance has intensified the need for novel therapeutics, including treatments with intrinsic transmission-blocking properties. In this study, we demonstrate that the isoprenoid abscisic acid (ABA) modulates signaling in the mammalian host to reduce parasitemia and the formation of transmissible gametocytes and in the mosquito host to reduce parasite infection. Oral ABA supplementation in a mouse model of malaria was well tolerated and led to reduced pathology and enhanced gene expression in the liver and spleen consistent with infection recovery. Oral ABA supplementation also increased mouse plasma ABA to levels that can signal in the mosquito midgut upon blood ingestion. Accordingly, we showed that supplementation of a Plasmodium falciparum-infected blood meal with ABA increased expression of mosquito nitric oxide synthase and reduced infection prevalence in a nitric oxide-dependent manner. Identification of the mechanisms whereby ABA reduces parasite growth in mammals and mosquitoes could shed light on the balance of immunity and metabolism across eukaryotes and provide a strong foundation for clinical translation.

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Section: Discussionsupporting

confidence: 55%

Supplementation with Abscisic Acid Reduces Malaria Disease Severity and Parasite Transmission

Glennon¹,

Adams²,

Hicks³

et al. 2016

The American Journal of Tropical Medicine and Hygiene

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“…The molecular mechanism(s) that explain(s) how this compound down‐modulates the release of proinflammatory mediators is yet to be deciphered; however, it is known that Rosiglitazone regulates Toll‐like receptor (TLR) signalling in immune cells,146 and controls (increases) the expression of CD36 in innate immune cells146 via cross‐regulation147; therefore, this might provide insights to how Rosiglitazone modulates the proinflammatory responses in immune cells. Interestingly, it was also observed in this clinical trial that the administration of Rosiglitazone led to lower parasite clearance time 145. This observation might be explained from another study, which showed that Rosiglitazone preferentially increases the expression of CD36 on macrophages146 with minimal effect on endothelial cells148 and this would potentially lead to increased phagocytosis by these cells 149.…”

Section: Taking Advantage Of Immune Regulationsupporting

confidence: 53%

Evaluating antidisease immunity to malaria and implications for vaccine design

Ademolue

Awandare

2017

Immunology

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SummaryImmunity to malaria could be categorized broadly as antiparasite or antidisease immunity. While most vaccine research efforts have focused on antiparasite immunity, the evidence from endemic populations suggest that antidisease immunity is an important component of natural immunity to malaria. The processes that mediate antidisease immunity have, however, attracted little to no attention, and most interests have been directed towards the antibody responses. This review evaluates the evidence for antidisease immunity in endemic areas and discusses the possible mechanisms responsible for it. Given the key role that inflammation plays in the pathogenesis of malaria, regulation of the inflammatory response appears to be a major mechanism for antidisease immunity in naturally exposed individuals.

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“…The authors demonstrated that rosiglitazone was a well-tolerated adjunct to standard therapy for non-severe Plasmodium falciparum malaria. In this case, rosiglitazone enhanced parasite clearance and decreased levels of inflammatory biomarkers that have been associated with adverse malaria outcomes (Boggild et al 2009). In the present paper, we demonstrate that treatment with 15d-PGJ 2 reduces inflammatory infiltration and decreases the size of amastigote nests in the cardiac tissue of T. cruzi-infected animals.…”

Section: Discussionmentioning

confidence: 99%

15d-PGJ2 modulates acute immune responses to Trypanosoma cruzi infection

Rodrigues

Miguel

Chica

et al. 2010

Mem. Inst. Oswaldo Cruz

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The acute phase of Trypanosoma cruzi infection is associated with a strong inflammatory reaction in the heart characterised by a massive infiltration of immune cells that is dependent on the T. cruzi strain and the host response. 15d-PGJ2 belongs to a new class of anti-inflammatory compounds with possible clinical applications. We evaluated the effects of 15d-PGJ2 administered during the acute phase of T. cruzi infection in mice. Mice were infected with the Colombian strain of T. cruzi and subsequently treated with 15d-PGJ2 repeatedly for seven days. The inflammatory infiltrate was examined by histologic analysis. Slides were immunohistochemically stained to count the number and the relative size of parasite nests. Infection-induced changes in serum cytokine levels were measured by ELISA. The results demonstrated that treatment with 15d-PGJ2 reduced the inflammatory infiltrate in the skeletal muscle at the site of infection and decreased the number of lymphocytes and neutrophils in the blood. In addition, we found that 15d-PGJ2 led to a decrease in the relative volume density of amastigote nests in cardiac muscle. T. cruzi-infected animals treated with 15d-PGJ2 displayed a statistically significant increase in IL-10 levels with no change in IFN-γ levels. Taken together, we demonstrate that treatment with 15d-PGJ2 in the acute phase of Chagas disease led to a controlled immune response with decreased numbers of amastigote nests, as measured by the volume density

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Use of Peroxisome Proliferator‐Activated Receptor γ Agonists as Adjunctive Treatment forPlasmodium falciparumMalaria: A Randomized, Double‐Blind, Placebo‐Controlled Trial

Abstract: ClinicalTrials.gov identifier NCT00149383 .

Cited by 70 publications

References 36 publications

Supplementation with Abscisic Acid Reduces Malaria Disease Severity and Parasite Transmission

Supplementation with Abscisic Acid Reduces Malaria Disease Severity and Parasite Transmission

Evaluating antidisease immunity to malaria and implications for vaccine design

15d-PGJ2 modulates acute immune responses to Trypanosoma cruzi infection

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