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Combinatorial therapy for blood-stage Plasmodium infection: A therapeutic mix encompassing  Ketorolac (Trade name: Toradol, Acular, Sprix] and Aspirin (anti-inflammatory drugs) decreases the expression of CTLA-4, PD-L1 and LAG-3, promotes CD4+ T-cell function, increases secretion of protective antibodies, promotes and clear blood-stage malaria via up regulation of its target gene, 21/February/2018, 6.13 am

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Introduction: What they say

A study from the Department of Microbiology and Immunology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA shows that “Regulatory T cells impede acute and long-term immunity to blood-stage malaria through CTLA-4.” This research paper was published, in September 2017 issue of the journal “Nature Medicine” [One of the best research journals in General biology with an I.F of 28.710], by Prof. Harty J and his research team members.

In connection with the study presented above, Prof. Harty J’s research team members had earlier shown that “Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection.” This research paper was published in December 2011 issue of the journal “Nature Immunology” [One of the best research journals in General biology with an I.F of 28.710].


What we say:

On the foundation of these interesting findings, Dr L Boominathan PhD, Director-cum-chief Scientist of GBMD, reports that:   Combinatorial therapy for blood-stage Plasmodium infection: A therapeutic mix encompassing  Ketorolac (Trade name: Toradol, Acular, Sprix] and Aspirin (anti-inflammatory drugs) decreases the expression of CTLA-4, PD-L1 and LAG-3, promotes CD4+ T-cell function, increases secretion of protective antibodies, promotes and clear blood-stage malaria via up regulation of its target gene


From significance of the study to Public health relevance:

Given that: (1) 214 million new cases of malaria had been reported in 2015; (2) nearly 438,000 people out of 214 million people who were infected with Malaria have died in 2015; (3) malaria has the potential to affect nearly half the global population; (4) molecular pathways involved and the mechanism of development of drug-resistant malaria is far from understood; (4) treating drug-resistant malaria is still a daunting task; (5) millions of deaths occur due to malaria every year; (6) out of the 125 million international travellers who visit countries, such as Ivory Coast, Angola, Burkina Faso, Burkina Faso, Mozambique and Mali, more than 30, 000 contract the disease; (7) most of the Malaria cases are registered in countries, such as sub-Saharan Africa—that cannot afford high-cost required for the treatment of drug-resistant malaria—compared to developed countries, such as US (10,000 malaria cases/ per year) and UK (1,500 malaria cases/year), (8) humans could not mount immunity against blood stage-malaria; and prevent re-infections; (9) billions of dollars are being spent each year globally for the treatment of Malaria, there is an urgent need to find: (i) a way to inhibit drug-resistant malaria; and (ii) a side-effect-free-Natural product-based drug that prevents relapse/recurrence of blood-stage/drug-resistant Malaria.


What is known?

Prof. Hardy’s research team has shown that blockade of CTLA-4, PD-1 ligand PD-L1 and the inhibitory receptor LAG-3: a) promote CD4+ T-cell function; b) increase the number of follicular helper T cells, germinal-center B cells etc.,; c) enhance the levels of protective antibodies; d) augment parasite clearance; e) promote species-transcending immunity to blood-stage malaria; f) prevent reinfection through potentiation of adaptive immunity; and g) clear blood-stage malaria, suggesting that inhibiting the expression of immune evasion molecules, such as CTLA-4, PD-1, PD-L1 and LAG-3, may attenuate chronic malaria-driven T-cell dysfunction; and promote parasite clearance in blood-stage malaria.


From research findings to Therapeutic opportunity:

This study suggests a small molecule-based combination therapy for blood-stage malaria. Both  Ketorolac and Aspirin have been shown to function as anti-inflammatory agents. However, this study has repurposed their function and suggest they may aid in the treatment of blood-stage malaria.

A therapeutic mix encompassing Ketorolac and Aspirin, by increasing the expression of its target gene, it may decrease the expression of immune evasion molecules, such as CTLA-4, PD-1, PD-L1 and LAG-3 (Figure 1). Thereby, it may: (1) increase CD4+ T-cell function; (2) augment the number of helper T cells, germinal-center B cells etc.,; (3) increase secretion of protective antibodies; (4) promote plasmodium parasite clearance; (5) mount acute and long-term immunity to blood-stage malaria; (6) stifle reinfection through induction of adaptive immunity;(7) clear blood-stage malaria. Thus, pharmacological formulations encompassing ” Ketorolac and Aspirin  or their analogues, either alone or in combination with other antimalarial drugs” may be used to treat blood-stage malaria (Figures 1-2).

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Figure 1 Mechanistic insights into how a therapeutic mix encompassing  Ketorolac and Aspirin inhibits blood stage malaria. Fisetin inhibits the expression of CTLA-4, PD-1, PD-L1 and LAG-3 via up regulation of its target genes

Figure 2. The chemical structure of Rifampisin and Aspirin.


Details of the research findings:

Idea Proposed/Formulated (with experimental evidence) by: Dr L Boominathan Ph.D.

Terms & Conditions apply http://genomediscovery.org/registration/terms-and-conditions/

Undisclosed mechanistic information: How does  a therapeutic mix encompassing  Ketorolac and Aspirin decrease the expression of CTLA-4, PD-1, PD-L1 and LAG-3?

Amount: $750#

For payment and purchase details, you may reach us at admin@genomediscovery.org

# Research cooperation


References:

Web: http://genomediscovery.org or http://newbioideas.com

Citation: Boominathan, L.,  Combinatorial therapy for blood-stage Plasmodium infection: A therapeutic mix encompassing  Ketorolac (Trade name: Toradol, Acular, Sprix] and Aspirin (anti-inflammatory drugs) decreases the expression of CTLA-4, PD-L1 and LAG-3, promotes CD4+ T-cell function, increases secretion of protective antibodies, promotes and clear blood-stage malaria via up regulation of its target gene, 21/February/2018, 6.13 am, Genome-2-Bio-Medicine Discovery center (GBMD), http://genomediscovery.org

Courtesy: When you cite, drop us a line at admin@genomediscovery.org

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