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      Dimethyl fumarate reduces TNF and Plasmodium falciparum induced brain endothelium activation in vitro

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          Abstract

          Background

          Cerebral malaria (CM) is associated with morbidity and mortality despite the use of potent anti-malarial agents. Brain endothelial cell activation and dysfunction from oxidative and inflammatory host responses and products released by Plasmodium falciparum-infected erythrocytes (IE), are likely the major contributors to the encephalopathy, seizures, and brain swelling that are associated with CM. The development of adjunctive therapy to reduce the pathological consequences of host response pathways could improve outcomes. A potentially protective role of the nuclear factor E2-related factor 2 (NRF2) pathway, which serves as a therapeutic target in brain microvascular diseases and central nervous system (CNS) inflammatory diseases such as multiple sclerosis was tested to protect endothelial cells in an in vitro culture system subjected to tumour necrosis factor (TNF) or infected red blood cell exposure. NRF2 is a transcription factor that mediates anti-oxidant and anti-inflammatory responses.

          Methods

          To accurately reflect clinically relevant parasite biology a unique panel of parasite isolates derived from patients with stringently defined CM was developed. The effect of TNF and these parasite lines on primary human brain microvascular endothelial cell (HBMVEC) activation in an in vitro co-culture model was tested. HBMVEC activation was measured by cellular release of IL6 and nuclear translocation of NFκB. The transcriptional and functional effects of dimethyl fumarate (DMF), an FDA approved drug which induces the NRF2 pathway, on host and parasite induced HBMVEC activation was characterized. In addition, the effect of DMF on parasite binding to TNF stimulated HBMVEC in a semi-static binding assay was examined.

          Results

          Transcriptional profiling demonstrates that DMF upregulates the NRF2-Mediated Oxidative Stress Response, ErbB4 Signaling Pathway, Peroxisome Proliferator-activated Receptor (PPAR) Signaling and downregulates iNOS Signaling and the Neuroinflammation Signaling Pathway on TNF activated HBMVEC. The parasite lines derived from eight paediatric CM patients demonstrated increased binding to TNF activated HBMVEC and varied in their binding and activation of HBMVEC. Overall DMF reduced both TNF and CM derived parasite activation of HBMVEC.

          Conclusions

          These findings provide evidence that targeting the NRF2 pathway in TNF and parasite activated HBMVEC mediates multiple protective pathways and may represent a novel adjunctive therapy to improve infection outcomes in CM.

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          Most cited references80

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          Human malaria parasites in continuous culture

          Plasmodium falciparum can now be maintained in continuous culture in human erythrocytes incubated at 38 degrees C in RPMI 1640 medium with human serum under an atmosphere with 7 percent carbon dioxide and low oxygen (1 or 5 percent). The original parasite material, derived from an infected Aotus trivirgatus monkey, was diluted more than 100 million times by the addition of human erythrocytes at 3- or 4-day intervals. The parasites continued to reproduce in their normal asexual cycle of approximately 48 hours but were no longer highly synchronous. The have remained infective to Aotus.
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            Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.

            BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsing-remitting multiple sclerosis. We conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing-remitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI. The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twice-daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P=0.005) and 34% with BG-12 thrice daily (P=0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T(2)-weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels. In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number, NCT00420212.).
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              Regulation of NF-κB by TNF family cytokines.

              The NF-κB family of inducible transcription factors is activated in response to a variety of stimuli. Amongst the best-characterized inducers of NF-κB are members of the TNF family of cytokines. Research on NF-κB and TNF have been tightly intertwined for more than 25 years. Perhaps the most compelling examples of the interconnectedness of NF-κB and the TNF have come from analysis of knock-out mice that are unable to activate NF-κB. Such mice die embryonically, however, deletion of TNF or TNFR1 can rescue the lethality thereby illustrating the important role of NF-κB as the key regulator of transcriptional responses to TNF. The physiological connections between NF-κB and TNF cytokines are numerous and best explored in articles focusing on a single TNF family member. Instead, in this review, we explore general mechanisms of TNF cytokine signaling, with a focus on the upstream signaling events leading to activation of the so-called canonical and noncanonical NF-κB pathways by TNFR1 and CD40, respectively.
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                Author and article information

                Contributors
                johanna.daily@einsteinmed.org
                Journal
                Malar J
                Malar J
                Malaria Journal
                BioMed Central (London )
                1475-2875
                21 October 2020
                21 October 2020
                2020
                : 19
                : 376
                Affiliations
                [1 ]GRID grid.251993.5, ISNI 0000000121791997, Department of Microbiology & Immunology and Infectious Diseases, , Albert Einstein College of Medicine, ; Bronx, NY USA
                [2 ]GRID grid.53964.3d, ISNI 0000 0004 0463 2611, Seattle Biomedical Research Institute, ; Seattle, WA USA
                [3 ]GRID grid.251993.5, ISNI 0000000121791997, Division of Infectious Diseases, Department of Medicine, , Albert Einstein College of Medicine, ; Bronx, NY USA
                [4 ]GRID grid.10595.38, ISNI 0000 0001 2113 2211, Blantyre Malaria Project, , University of Malawi College of Medicine, ; Blantyre 3, Malawi
                [5 ]GRID grid.17088.36, ISNI 0000 0001 2150 1785, Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, , Michigan State University, ; East Lansing, MI USA
                [6 ]GRID grid.240741.4, ISNI 0000 0000 9026 4165, Seattle Children’s Research Institute, ; Seattle, WA USA
                [7 ]GRID grid.34477.33, ISNI 0000000122986657, Department of Global Health, , University of Washington, ; Seattle, WA USA
                [8 ]Present Address: Department of Research in Parasitology, Gorgas Memorial Research Institute for Health Studies, Panama City, Panama
                Author information
                http://orcid.org/0000-0003-2506-1072
                Article
                3447
                10.1186/s12936-020-03447-7
                7579885
                33087130
                f4599227-a6fe-4fa8-91a4-87a3b42a597e
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 18 April 2020
                : 16 October 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R01AI077623
                Award ID: RO1AI141602
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

                Infectious disease & Microbiology
                nrf2 pathway,cerebral malaria,human brain microvascular endothelial cell activation,il-6,dimethyl fumarate,nuclear factor κb,tnf,icam1,epcr

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