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https://www.arca.fiocruz.br/handle/icict/24911
TEMPOL, AN INTRACELLULAR ANTIOXIDANT, INHIBITS TISSUE FACTOR EXPRESSION, ATTENUATES DENDRITIC CELL FUNCTION, AND IS PARTIALLY PROTECTIVE IN A MURINE MODEL OF CEREBRAL MALARIA
Células dendríticas
Reação em cadeia da polimerase em tempo real
Antioxidantes
Plasmodium Falciparum
Dendritic Cells
Real-Time Polymerase Chain Reaction
Antioxidants
Plasmodium Falciparum
Author
Francischetti, Ivo M. B
Gordon, Emile
Bizzarro, Bruna
Gera, Nidhi
Andrade, Bruno de Bezerril
Oliveira, Fabiano
Ma, Dongying
Assumpção, Teresa Cristina França
Ribeiro, José M. C
Pena, Mirna
Qi, Chen-Feng
Diouf, Ababacar
Moretz, Samuel E
Long, Carole A
Ackerman, Hans C
Pierce, Susan K
Nunes, Anderson Sá
Waisberg, Michael
Gordon, Emile
Bizzarro, Bruna
Gera, Nidhi
Andrade, Bruno de Bezerril
Oliveira, Fabiano
Ma, Dongying
Assumpção, Teresa Cristina França
Ribeiro, José M. C
Pena, Mirna
Qi, Chen-Feng
Diouf, Ababacar
Moretz, Samuel E
Long, Carole A
Ackerman, Hans C
Pierce, Susan K
Nunes, Anderson Sá
Waisberg, Michael
Affilliation
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA
University of São Paulo. Institute of Biomedical Sciences. Laboratory of Experimental Immunology. Department of Immunology. São Paulo, SP, Brazil
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA
National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases. Bethesda, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA
University of São Paulo. Institute of Biomedical Sciences. Laboratory of Experimental Immunology. Department of Immunology. São Paulo, SP, Brazil
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA / University of Virginia. Department of Pathology. Charlottesville, Virginia, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA
University of São Paulo. Institute of Biomedical Sciences. Laboratory of Experimental Immunology. Department of Immunology. São Paulo, SP, Brazil
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA
National Institute of Allergy and Infectious Diseases. Laboratory of Parasitic Diseases. Bethesda, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Malaria and Vector Research. Rockville, MD, USA
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA
University of São Paulo. Institute of Biomedical Sciences. Laboratory of Experimental Immunology. Department of Immunology. São Paulo, SP, Brazil
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Laboratory of Immunogenetics. Rockville, MD, USA / University of Virginia. Department of Pathology. Charlottesville, Virginia, USA
Abstract
The role of intracellular radical oxygen species (ROS) in pathogenesis of cerebral malaria (CM) remains incompletely understood. Methods and Findings: We undertook testing Tempol—a superoxide dismutase (SOD) mimetic and pleiotropic intracellular
antioxidant—in cells relevant to malaria pathogenesis in the context of coagulation and inflammation. Tempol was also
tested in a murine model of CM induced by Plasmodium berghei Anka infection. Tempol was found to prevent transcription
and functional expression of procoagulant tissue factor in endothelial cells (ECs) stimulated by lipopolysaccharide (LPS). This
effect was accompanied by inhibition of IL-6, IL-8, and monocyte chemoattractant protein (MCP-1) production. Tempol also
attenuated platelet aggregation and human promyelocytic leukemia HL60 cells oxidative burst. In dendritic cells, Tempol
inhibited LPS-induced production of TNF-a, IL-6, and IL-12p70, downregulated expression of co-stimulatory molecules, and
prevented antigen-dependent lymphocyte proliferation. Notably, Tempol (20 mg/kg) partially increased the survival of mice
with CM. Mechanistically, treated mice had lowered plasma levels of MCP-1, suggesting that Tempol downmodulates EC
function and vascular inflammation. Tempol also diminished blood brain barrier permeability associated with CM when
started at day 4 post infection but not at day 1, suggesting that ROS production is tightly regulated. Other antioxidants—
such as a-phenyl N-tertiary-butyl nitrone (PBN; a spin trap), MnTe-2-PyP and MnTBAP (Mn-phorphyrin), Mitoquinone (MitoQ)
and Mitotempo (mitochondrial antioxidants), M30 (an iron chelator), and epigallocatechin gallate (EGCG; polyphenol from
green tea) did not improve survival. By contrast, these compounds (except PBN) inhibited Plasmodium falciparum growth in
culture with different IC50s. Knockout mice for SOD1 or phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)
oxidase (gp91phox–/–) or mice treated with inhibitors of SOD (diethyldithiocarbamate) or NADPH oxidase (diphenyleneiodonium)
did not show protection or exacerbation for CM.
Conclusion: Results with Tempol suggest that intracellular ROS contribute, in part, to CM pathogenesis. Therapeutic
targeting of intracellular ROS in CM is discussed.
Keywords in Portuguese
Malaria cerebralCélulas dendríticas
Reação em cadeia da polimerase em tempo real
Antioxidantes
Plasmodium Falciparum
Keywords
Malaria cerebralDendritic Cells
Real-Time Polymerase Chain Reaction
Antioxidants
Plasmodium Falciparum
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