flavin-adenine-dinucleotide and Malaria

Topics: Animals; Antimalarials; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Malaria; Mice; Plasmodium falciparum; Riboflavin

Malaria is the most common disease transmitted by the bite by an infected female anopheles mosquito and caused by the plasmodium parasite. It is mostly prevalent in subtropical regions receiving abundant rain and supporting copious mosquito breeding. This disease is generally detected by the microscopic examination of blood films or antigen based rapid diagnostic test. Only occasionally the parasite DNA is detected using polymerase chain reaction in certain advanced, expensive laboratories.. An innovative spectral detection method based on the fluorescence spectra of a set of blood plasma biomolecules [tyrosine, tryptophan, nicotinamide adenine dinucleotide (NAD), and flavin adenine dinucleotide (FAD)] and red blood cell (RBC)-associated porphyrin is being evolved by our group.. The research so far has exhibited sensitivity and specificity values exceeding 90% based on the spectral features of blood components of 14 malaria patients and 20 numbers of age adjusted normal controls. The fluorescent biomolecules go out of proportion when the malarial parasite breaks down the hemoglobin of blood.. This technique has the potential to be used as an alternative diagnostic procedure for malaria since the instrumentation involved is portable and inexpensive.. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_182.

Topics: Adolescent; Biomarkers; Case-Control Studies; Child; Female; Flavin-Adenine Dinucleotide; Humans; Malaria; Male; NAD; Porphyrins; Sensitivity and Specificity; Spectrometry, Fluorescence; Tryptophan; Tyrosine; Young Adult

Artemisinins are proposed to act in the malaria parasite cytosol by oxidizing dihydroflavin cofactors of redox-active flavoenzymes, and under aerobic conditions by inducing their autoxidation. Perturbation of redox homeostasis coupled with the generation of reactive oxygen species (ROS) ensues. Ascorbic acid-methylene blue (MB), N-benzyl-1,4-dihydronicotinamide (BNAH)-MB, BNAH-lumiflavine, BNAH-riboflavin (RF), and NADPH-FAD-E. coli flavin reductase (Fre) systems at pH 7.4 generate leucomethylene blue (LMB) and reduced flavins that are rapidly oxidized in situ by artemisinins. These oxidations are inhibited by the 4-aminoquinolines piperaquine (PPQ), chloroquine (CQ), and others. In contrast, the arylmethanols lumefantrine, mefloquine (MFQ), and quinine (QN) have little or no effect. Inhibition correlates with the antagonism exerted by 4-aminoquinolines on the antimalarial activities of MB, RF, and artemisinins. Lack of inhibition correlates with the additivity/synergism between the arylmethanols and artemisinins. We propose association via π complex formation between the 4-aminoquinolines and LMB or the dihydroflavins; this hinders hydride transfer from the reduced conjugates to the artemisinins. The arylmethanols have a decreased tendency to form π complexes, and so exert no effect. The parallel between chemical reactivity and antagonism or additivity/synergism draws attention to the mechanism of action of all drugs described herein. CQ and QN inhibit the formation of hemozoin in the parasite digestive vacuole (DV). The buildup of heme-Fe(III) results in an enhanced efflux from the DV into the cytosol. In addition, the lipophilic heme-Fe(III) complexes of CQ and QN that form in the DV are proposed to diffuse across the DV membrane. At the higher pH of the cytosol, the complexes decompose to liberate heme-Fe(III) . The quinoline or arylmethanol reenters the DV, and so transfers more heme-Fe(III) out of the DV. In this way, the 4-aminoquinolines and arylmethanols exert antimalarial activities by enhancing heme-Fe(III) and thence free Fe(III) concentrations in the cytosol. The iron species enter into redox cycles through reduction of Fe(III) to Fe(II) largely mediated by reduced flavin cofactors and likely also by NAD(P)H-Fre. Generation of ROS through oxidation of Fe(II) by oxygen will also result. The cytotoxicities of artemisinins are thereby reinforced by the iron. Other aspects of drug action are emphasized. In the cytosol or DV, association by π comp

Topics: Antimalarials; Artemisinins; Chloroquine; Drug Interactions; Ferric Compounds; Flavin-Adenine Dinucleotide; Humans; Malaria; Methylene Blue; NAD; NADP; Oxidative Stress; Quinolines; Riboflavin

Artemisinins rapidly oxidize leucomethylene blue (LMB) to methylene blue (MB); they also oxidize dihydroflavins such as the reduced conjugates RFH₂ of riboflavin (RF), and FADH₂ of the cofactor flavin adenine dinucleotide (FAD), to the corresponding flavins. Like the artemisinins, MB oxidizes FADH₂, but unlike artemisinins, it also oxidizes NAD(P)H. Like MB, artemisinins are implicated in the perturbation of redox balance in the malaria parasite by interfering with parasite flavoenzyme disulfide reductases. The oxidation of LMB by artemisinin is inhibited by chloroquine (CQ), an inhibition that is abruptly reversed by verapamil (VP). CQ also inhibits artemisinin-mediated oxidation of RFH₂ generated from N-benzyl-1,4-dihydronicotinamide (BNAH)-RF, or FADH₂ generated from NADPH or NADPH-Fre, an effect that is also modulated by verapamil. The inhibition likely proceeds by the association of LMB or dihydroflavin with CQ, possibly involving donor-acceptor or π complexes that hinder oxidation by artemisinin. VP competitively associates with CQ, liberating LMB or dihydroflavin from their respective CQ complexes. The observations explain the antagonism between CQ-MB and CQ-artemisinins in vitro, and are reconcilable with CQ perturbing intraparasitic redox homeostasis. They further suggest that a VP-CQ complex is a means by which VP reverses CQ resistance, wherein such a complex is not accessible to the putative CQ-resistance transporter (PfCRT).

Topics: Animals; Antimalarials; Artemisinins; Chloroquine; Drug Resistance; Drug Synergism; Flavin-Adenine Dinucleotide; Homeostasis; Humans; Malaria; Methylene Blue; Oxidation-Reduction; Verapamil

Topics: Animals; Apoenzymes; Binding Sites; Carmustine; Chromatography, Liquid; Dihydrolipoamide Dehydrogenase; Erythrocytes; Flavin-Adenine Dinucleotide; Glutathione; Glutathione Reductase; Humans; Isocyanates; Kinetics; Malaria; Mass Spectrometry; Myocardium; Oxidation-Reduction; Oxidative Stress; Sulfhydryl Compounds; Swine

Topics: Animals; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Flavins; Free Radicals; Humans; Malaria; Oxygen; Rats; Riboflavin; Riboflavin Deficiency

Topics: Brazil; Electrophoresis, Starch Gel; Erythrocytes; Flavin-Adenine Dinucleotide; Glucosephosphate Dehydrogenase; Glutathione; Glutathione Reductase; Humans; Indians, South American; Malaria; Polymorphism, Genetic