Effect of the pseudomonas metabolites HQNO on the Toxoplasma gondii RH strain in vitro and in vivo. (April 2023)

• Record Type: Journal Article
• Authors: Mo, Jiao; Si, Hongfei; Liu, Siyang; Zeng, Qingyuan; Cai, Minghao; Liu, Zhendi; Zhang, Jiyu; Fang, Jingjing; Zhang, Jili
• Is Part Of: International journal for parasitology. Volume 21(2023)
• Page Start: 74
• Page End: 80
• Publication Date: 2023-04
• Subjects: HQNO -- Toxoplasma gondii -- Invasion -- Proliferation -- Pharmacokinetics -- In vivo -- TEM; Transmission electron microscopy (TEM) -- Mitochondrial membrane potential (ΔΨm) -- Reactive oxygen species (ROS) -- Electron transport chain (ETC) -- Toxoplasma gondii (T. gondii) -- Type-Ⅱ NADH dehydrogenases (NDH-2) -- Endochin-like quinolone (ELQ) -- 2-Heptyl-4-hydroxyquinoline N-oxide (HQNO) -- Charge transfer complex (CTC) -- Mitochondrial membrane permeability transition pore (mPTP) -- Dissolved in dimethyl sulfoxide (DMSO) -- Dulbecco's modified Eagle's medium (DMEM) -- Foetal bovine serum (FBS) -- Nonessential amino acids (NEAAs) -- Parasitophorous vacuoles (PVs) -- 50% effective concentration (EC50) -- Standard deviation (SD) -- Akaike Information Criterion (AIC) -- Peak plasma concentration (Cmax) -- Area under the plasma curve (AUC) -- Half-life (T1/2) -- Peak time (Tmax) -- Adenosine triphosphate (ATP) -- hydroxy-2-dodecyl-4(1H) quinolone (HDQ) -- Half-maximal inhibitory concentration (IC50); Parasitic diseases -- Chemotherapy -- Periodicals; Drug resistance -- Periodicals; 616.96061
• DOI: 10.1016/j.ijpddr.2023.02.001
• Languages: English
• ISSNs: 2211-3207

Abstract

Abstract: Toxoplasmosis is a widespread disease in humans and animals. Currently, toxoplasmosis chemotherapy options are limited due to severe side effects. There is an urgent need to develop new drugs with better efficacy and few side effects. HQNO, a cytochrome bc 1 and type II NADH inhibitor in eukaryotes and bacteria, possesses extensive bioactivity. In this study, the cytotoxicity of HQNO was evaluated in Vero cells. The in vitro effects of HQNO were determined by plaque assay and qPCR assay. To determine the in vivo effect of HQNO, pharmacokinetic experiments and in vivo infection assays were performed in mice. The changes in tachyzoites after HQNO exposure were examined by transmission electron microscopy (TEM), MitoTracker Red CMXRos staining, ROS detection and ATP detection. HQNO inhibited T. gondii invasion and proliferation with an EC50 of 0.995 μM. Pharmacokinetic experiments showed that the Cmax of HQNO (20 mg/kg·bw) was 3560 ± 1601 ng/mL (13.73 μM) in healthy BALB/c mouse plasma with no toxicity in vivo . Moreover, HQNO induced a significant decrease in the parasite burden load of T. gondii in mouse peritoneum. TEM revealed alterations in the mitochondria of T. gondii . Further assays verified that HQNO also decreased the mitochondrial membrane potential (ΔΨm) and ATP levels and enhanced the level of reactive oxygen species (ROS) in T. gondii . Hence, HQNO exerted anti-T. gondii activity, which may be related to the damage to the mitochondrial electron transport chain (ETC). Graphical abstract: Image 1