FIG 1.

(Ai) Formalism indicating the irreversible reduction of the oxidant drug artemisinin by reduced conjugates of flavin cofactors flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and other reduced flavins, e.g., riboflavin (RF), to the inert deoxyartemisinin. (Aii) Redox cycling of methylene blue (MB) via its reduced conjugate, leucomethylene blue (LMB), initiated through reduction of MB by FADH₂ to LMB and reoxidation of the latter by oxygen to generate MB and reactive oxygen species (ROS). (B) Perturbation of redox homeostasis by artemisinin through oxidation of reduced flavin cofactors, e.g., reduced flavin adenine dinucleotide (FADH₂) of thioredoxin reductase (TrxR), glutathione reductase (GR), and other flavin disulfide reductases, resulting in the buildup of ROS; the artemisinin is thereby irreversibly reduced. Addition of MB maintains ROS generation via redox cycling through its reduced form, LMB, which is oxidized to MB with the concomitant generation of ROS; the reduction of MB to LMB by FADH₂ is complementary to the reduction of artemisinin to deoxyartemisinin by the same reduced cofactor, yet by reoxidation of the LMB to MB by oxygen, redox cycling now ensues with the sustained attrition of FADH₂.