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HQNO 假单胞菌代谢产物对体外和体内弓形虫 RH 株的影响。

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

机构信息

School of Medicine, Ningbo University, Ningbo, China.

College of Pharmacy, Jinan University, Guangzhou, China.

出版信息

Int J Parasitol Drugs Drug Resist. 2023 Apr;21:74-80. doi: 10.1016/j.ijpddr.2023.02.001. Epub 2023 Feb 4.

DOI:10.1016/j.ijpddr.2023.02.001
PMID:36758272
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9929485/
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 bc1 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 EC of 0.995 μM. Pharmacokinetic experiments showed that the C 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).

摘要

刚地弓形虫病是一种广泛存在于人类和动物中的疾病。目前，由于严重的副作用，弓形虫病的化学治疗选择有限。因此，迫切需要开发具有更好疗效和较少副作用的新药。 HQNO 是真核生物和细菌中细胞色素 bc1 和 II 型 NADH 的抑制剂，具有广泛的生物活性。在本研究中，评估了 HQNO 在 Vero 细胞中的细胞毒性。通过噬菌斑试验和 qPCR 试验确定 HQNO 的体外作用。为了确定 HQNO 的体内作用，在小鼠中进行了药代动力学实验和体内感染实验。通过透射电子显微镜（TEM）、MitoTracker Red CMXRos 染色、ROS 检测和 ATP 检测观察 HQNO 暴露后速殖子的变化。 HQNO 以 EC 为 0.995 μM 抑制弓形虫的侵袭和增殖。药代动力学实验表明，健康 BALB/c 小鼠血浆中 HQNO（20 mg/kg·bw）的 C 为 3560±1601 ng/mL（13.73 μM），体内无毒性。此外，HQNO 可显著降低小鼠腹膜内弓形虫的寄生虫负荷量。TEM 显示弓形虫的线粒体发生变化。进一步的试验证实，HQNO 还降低了线粒体膜电位（ΔΨm）和 ATP 水平，并增加了弓形虫中的活性氧（ROS）水平。因此， HQNO 发挥了抗弓形虫活性，这可能与线粒体电子传递链（ETC）的损伤有关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/808847f44950/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/d4ad10205222/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/594f99507282/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/3ed5f3f0088a/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/912bc1e575af/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/341c6b61d3d2/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/b2dd3388b7f5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/8b51e4011e31/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/808847f44950/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/d4ad10205222/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/594f99507282/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/3ed5f3f0088a/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/912bc1e575af/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/341c6b61d3d2/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/b2dd3388b7f5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/8b51e4011e31/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db58/9929485/808847f44950/gr7.jpg

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