Licarin-B Exhibits Activity Against the Toxoplasma gondii RH Strain by Damaging Mitochondria and Activating Autophagy

Toxoplasma gondii is an obligate intracellular pathogen that infects warm-blooded animals and humans. However, side effects limit toxoplasmosis treatment, and new drugs with high efficiency and low toxicity need to be developed. Natural products found in plants have become a useful source of drugs f...

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Main Authors: Jili Zhang, Hongfei Si, Kun Lv, Yanhua Qiu, Jichao Sun, Yubin Bai, Bing Li, Xuzheng Zhou, Jiyu Zhang
Format: Article
Language:English
Published: Frontiers Media S.A. 2021-06-01
Series:Frontiers in Cell and Developmental Biology
Subjects:
TEM
Online Access:https://www.frontiersin.org/articles/10.3389/fcell.2021.684393/full
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language English
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author Jili Zhang
Jili Zhang
Jili Zhang
Jili Zhang
Hongfei Si
Kun Lv
Yanhua Qiu
Yanhua Qiu
Yanhua Qiu
Jichao Sun
Jichao Sun
Jichao Sun
Yubin Bai
Yubin Bai
Yubin Bai
Bing Li
Bing Li
Bing Li
Xuzheng Zhou
Xuzheng Zhou
Xuzheng Zhou
Jiyu Zhang
Jiyu Zhang
Jiyu Zhang
spellingShingle Jili Zhang
Jili Zhang
Jili Zhang
Jili Zhang
Hongfei Si
Kun Lv
Yanhua Qiu
Yanhua Qiu
Yanhua Qiu
Jichao Sun
Jichao Sun
Jichao Sun
Yubin Bai
Yubin Bai
Yubin Bai
Bing Li
Bing Li
Bing Li
Xuzheng Zhou
Xuzheng Zhou
Xuzheng Zhou
Jiyu Zhang
Jiyu Zhang
Jiyu Zhang
Licarin-B Exhibits Activity Against the Toxoplasma gondii RH Strain by Damaging Mitochondria and Activating Autophagy
Frontiers in Cell and Developmental Biology
natural compounds
T. gondii
licarin-B
proliferation
TEM
author_facet Jili Zhang
Jili Zhang
Jili Zhang
Jili Zhang
Hongfei Si
Kun Lv
Yanhua Qiu
Yanhua Qiu
Yanhua Qiu
Jichao Sun
Jichao Sun
Jichao Sun
Yubin Bai
Yubin Bai
Yubin Bai
Bing Li
Bing Li
Bing Li
Xuzheng Zhou
Xuzheng Zhou
Xuzheng Zhou
Jiyu Zhang
Jiyu Zhang
Jiyu Zhang
author_sort Jili Zhang
title Licarin-B Exhibits Activity Against the Toxoplasma gondii RH Strain by Damaging Mitochondria and Activating Autophagy
title_short Licarin-B Exhibits Activity Against the Toxoplasma gondii RH Strain by Damaging Mitochondria and Activating Autophagy
title_full Licarin-B Exhibits Activity Against the Toxoplasma gondii RH Strain by Damaging Mitochondria and Activating Autophagy
title_fullStr Licarin-B Exhibits Activity Against the Toxoplasma gondii RH Strain by Damaging Mitochondria and Activating Autophagy
title_full_unstemmed Licarin-B Exhibits Activity Against the Toxoplasma gondii RH Strain by Damaging Mitochondria and Activating Autophagy
title_sort licarin-b exhibits activity against the toxoplasma gondii rh strain by damaging mitochondria and activating autophagy
publisher Frontiers Media S.A.
series Frontiers in Cell and Developmental Biology
issn 2296-634X
publishDate 2021-06-01
description Toxoplasma gondii is an obligate intracellular pathogen that infects warm-blooded animals and humans. However, side effects limit toxoplasmosis treatment, and new drugs with high efficiency and low toxicity need to be developed. Natural products found in plants have become a useful source of drugs for toxoplasmosis. In this study, twenty natural compounds were screened for anti-T. gondii activity by Giemsa staining or real-time fluorescence quantitative polymerase chain reaction (qPCR) in vitro. Among these, licarin-B from nutmeg exhibited excellent anti-T. gondii activity, inhibiting T. gondii invasion and proliferation in a dose-dependent manner, with an EC50 of 14.05 ± 3.96 μg/mL. In the in vivo, licarin-B treatment significantly reduced the parasite burden in tissues compared to no treatment, protected the 90% infected mice from to death at 50 mg/kg.bw. Flow cytometry analysis suggested a significant reduction in T. gondii survival after licarin-B treatment. Ultrastructural changes in T. gondii were observed by transmission electron microscopy (TEM), as licarin-B induced mitochondrial swelling and formation of cytoplasmic vacuoles, an autophagosome-like double-membrane structure and extensive clefts around the T. gondii nucleus. Furthermore, MitoTracker Red CMXRos, MDC, and DAPI staining showed that licarin-B promoted mitochondrial damage, autophagosome formation, and nuclear disintegration, which were consistent with the TEM observations. Together, these findings indicate that licarin-B is a promising anti-T. gondii agent that potentially functions by damaging mitochondria and activating autophagy, leading to T. gondii death.
topic natural compounds
T. gondii
licarin-B
proliferation
TEM
url https://www.frontiersin.org/articles/10.3389/fcell.2021.684393/full
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spelling doaj-cc83c61d50994ab1b92b25571e5b7bd82021-06-11T11:21:17ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2021-06-01910.3389/fcell.2021.684393684393Licarin-B Exhibits Activity Against the Toxoplasma gondii RH Strain by Damaging Mitochondria and Activating AutophagyJili Zhang0Jili Zhang1Jili Zhang2Jili Zhang3Hongfei Si4Kun Lv5Yanhua Qiu6Yanhua Qiu7Yanhua Qiu8Jichao Sun9Jichao Sun10Jichao Sun11Yubin Bai12Yubin Bai13Yubin Bai14Bing Li15Bing Li16Bing Li17Xuzheng Zhou18Xuzheng Zhou19Xuzheng Zhou20Jiyu Zhang21Jiyu Zhang22Jiyu Zhang23Ningbo University School of Medicine, Ningbo, ChinaLanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, ChinaKey Laboratory of New Animal Drug Project of Gansu Province, Lanzhou, ChinaKey Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou, ChinaCollege of Pharmacy, Jinan University, Guangzhou, ChinaNingbo University School of Business, Ningbo, ChinaLanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, ChinaKey Laboratory of New Animal Drug Project of Gansu Province, Lanzhou, ChinaKey Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou, ChinaLanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, ChinaKey Laboratory of New Animal Drug Project of Gansu Province, Lanzhou, ChinaKey Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou, ChinaLanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, ChinaKey Laboratory of New Animal Drug Project of Gansu Province, Lanzhou, ChinaKey Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou, ChinaLanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, ChinaKey Laboratory of New Animal Drug Project of Gansu Province, Lanzhou, ChinaKey Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou, ChinaLanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, ChinaKey Laboratory of New Animal Drug Project of Gansu Province, Lanzhou, ChinaKey Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou, ChinaLanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou, ChinaKey Laboratory of New Animal Drug Project of Gansu Province, Lanzhou, ChinaKey Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture, Lanzhou, ChinaToxoplasma gondii is an obligate intracellular pathogen that infects warm-blooded animals and humans. However, side effects limit toxoplasmosis treatment, and new drugs with high efficiency and low toxicity need to be developed. Natural products found in plants have become a useful source of drugs for toxoplasmosis. In this study, twenty natural compounds were screened for anti-T. gondii activity by Giemsa staining or real-time fluorescence quantitative polymerase chain reaction (qPCR) in vitro. Among these, licarin-B from nutmeg exhibited excellent anti-T. gondii activity, inhibiting T. gondii invasion and proliferation in a dose-dependent manner, with an EC50 of 14.05 ± 3.96 μg/mL. In the in vivo, licarin-B treatment significantly reduced the parasite burden in tissues compared to no treatment, protected the 90% infected mice from to death at 50 mg/kg.bw. Flow cytometry analysis suggested a significant reduction in T. gondii survival after licarin-B treatment. Ultrastructural changes in T. gondii were observed by transmission electron microscopy (TEM), as licarin-B induced mitochondrial swelling and formation of cytoplasmic vacuoles, an autophagosome-like double-membrane structure and extensive clefts around the T. gondii nucleus. Furthermore, MitoTracker Red CMXRos, MDC, and DAPI staining showed that licarin-B promoted mitochondrial damage, autophagosome formation, and nuclear disintegration, which were consistent with the TEM observations. Together, these findings indicate that licarin-B is a promising anti-T. gondii agent that potentially functions by damaging mitochondria and activating autophagy, leading to T. gondii death.https://www.frontiersin.org/articles/10.3389/fcell.2021.684393/fullnatural compoundsT. gondiilicarin-BproliferationTEM