EXPERIMENTAL PARASITOLOGY
·
2016
·
IF 1.623
Xiaochuan Zhang,Lili Jin,Zhe Cui,Changhao Zhang,Xue Wu,Hyun Park,Hongmei Quan,Chunmei Jin
Toxoplasma gondii ( T . gondii ) is an important pathogen which can causes serious public health problems. Since the current therapeutic drugs for toxoplasmosis present serious host toxicity, research on effective and new substances of relatively low toxicity is urgently needed. This study was carried out to evaluate the anti-parasitic effect of oxymatrine (OM) and matrine (ME) against T . gondii in vitro and in vivo . In our study, the anti- T . gondii activities of ME and OM were evaluated in vitro using cell counting kit-8 assay, morphological observation and trypan blue exclusion assay. In vivo , mice were sacrificed four days post-infection and ascites were drawn out to determine the extent of tachyzoite proliferation. Viscera indexes and liver biochemical parameters, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutathione (GSH) and malondialdehyde (MDA), were examined to evaluate the toxicity of compounds to mice. As a result, OM and ME showed anti- T . gondii activity but low selectivity toxicity to HeLa cells. Both compounds also significantly decreased the number of tachyzoites in peritoneal cavity and recovered the levels of ALT, AST, GSH and MDA in liver. Moreover, the mice treated with OM or ME achieved better results in viscera index and survival rate than that of spiramycin. These results suggest that OM and ME are likely the sources of new drugs for toxoplasmosis, and further studies will be necessary to compare the efficacy of drug combination, as well as identify its action of mechanism.
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MOLECULES
·
2024
·Vol. 29
·期 21
·5024
·
IF 4.2
Jieqiong Wang,Weifeng Yan,Xu Cheng,Yonggang Tong,Sihong Wang,Chunmei Jin
Toxoplasmosis, a zoonotic infection caused byToxoplasma gondii(T. gondii), poses a significant risk to human health and public safety. Despite the availability of clinical treatments, none effectively mitigate the intestinal barrier damage, which is the primary defense againstT. gondiiinvasion. This study introduced aldehyde groups into the indole scaffold of a peptide-like structure to investigate the protective effects of these indole aldehyde derivatives on the intestinal barrier in mice with acuteT. gondiiinfection. This approach leveraged the propensity of peptides and aldehyde groups to form hydrogen bonds. We synthesized a range of indole derivatives using the Vilsmeier–Haack reaction and evaluated their intestinal barrier protective effects both in vitro and in vivo. Our findings revealed that indole derivativesA1(1-Formyl-1H-indole-3-acetonitrile),A3(Indole-3-carboxaldehyde),A5(2-Chloro-1H-indole-3-carboxaldehyde),A8(1-Methyl-indole-3-carboxaldehyde), andA9(1-Methyl-2-phenyl-1H-indole-3-carboxaldehyde) demonstrated a higher selectivity index compared to the positive control, spiramycin. These derivatives enhanced gastrointestinal motility, increased glutathione (GSH) levels in the small intestine, and reduced malondialdehyde (MDA) and nitric oxide (NO) levels in the small intestine tissue and diamine oxidase (DAO) and NO levels in the serum of infected mice. Notably,A3exhibited comparable anti-T. gondiitachyzoites activity in the peritoneal cavity. Molecular docking studies indicated that the aldehyde group on the indole scaffold not only formed a hydrogen bond with NTPase-II but also interacted with TgCDPK1 through hydrogen bonding. Among the derivatives,A3showed promising intestinal barrier protective effects in mice with acuteT. gondiiinfection. This research suggests that indole derivatives could serve as a potential therapeutic strategy for intestinal diseases induced byT. gondii,offering a novel direction for treating intestinal barrier damage and providing valuable insights for the chemical modification of drugs targetingT. gondii. Furthermore, it contributes to the advancement of therapeutic approaches for toxoplasmosis.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 24
·期 1
·229
·
IF 6.208
Mao Huang,Xinru Cao,Yucong Jiang,Yuehong Shi,Yazhen Ma,Dandan Hu,Xingju Song
Toxoplasma gondiiis a widespread intracellular pathogen that infects humans and a variety of animals. Dihydroartemisinin (DHA), an effective anti-malarial drug, has potential anti-T. gondiiactivity that induces ferroptosis in tumor cells, but the mechanism by which it killsT. gondiiis not fully understood. In this study, the mechanism of DHA inhibitingT. gondiigrowth and its possible drug combinations are described. DHA potently inhibitedT. gondiiwith a half-maximal effective concentration (EC50) of 0.22 μM. DHA significantly increased the ROS level of parasites and decreased the mitochondrial membrane potential, which could be reversed by ferroptosis inhibitors (DFO). Moreover, the ferroptosis inducer RSL3 inhibitedT. gondiiwith an EC50of 0.75 μM. In addition, RSL3 enhanced the DHA-induced ROS level, and the combination of DHA and RSL3 significantly increased the anti-Toxoplasmaeffect as compared to DHA alone. In summary, we found that DHA-induced ROS accumulation in tachyzoites may be an important cause ofT. gondiigrowth inhibition. Furthermore, we found that the combination of DHA and RSL3 may be an alternative to toxoplasmosis. These results will provide a new strategy for anti-Toxoplasmadrug screening and clinical medication guidance.Keywords:Toxoplasma gondii;dihydroartemisinin;ferroptosis inducer RSL3;mitochondrial membrane potential;ROS
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PARASITOLOGY RESEARCH
·
2019
·Vol. 118
·期 3
·935-944
·
IF 2.067
Ye Shu,Xia Ningbo,Zhao Pengfei,Yang Jichao,Zhou Yanqin,Shen Bang,Zhao Junlong
Toxoplasma gondii is a ubiquitous parasitic protozoan infecting humans and a wide variety of animals. Fast-replicating tachyzoites during acute infection and slowly growing bradyzoites during chronic infection are the two basic forms of T. gondii in intermediate hosts. Interconversion between the two contributes to the transmission and pathogenesis of this parasite. Secretory micronemal proteins are thought to mediate interactions with host cells and facilitate parasite invasion, therefore the majority of them are highly expressed in tachyzoites. Micronemal protein 13 (MIC13) is unique in that its expression is low in tachyzoites and is upregulated under bradyzoite-inducing conditions. Previous attempts to disrupt this gene were not successful, implying that it may play critical roles during parasite growth. However, in this study, MIC13 was successfully disrupted in type 1 strain RH and type 2 strain ME49 using CRISPR/Cas9-mediated gene disruption techniques. Consistent with its low expression in tachyzoites and increased expression under stress or bradyzoite-inducing conditions, MIC13-inactivated mutants displayed normal growth, host cell invasion, intracellular replication, and egress, as well as acute virulence at the tachyzoite stage. However, under stress conditions, such as high pH or oxygen limitation, MIC13-disrupted parasites showed significantly slower growth rates compared to the parental strains, suggesting that it is required for optimal parasite growth under bradyzoite-inducing or stress conditions. This is the first micronemal protein reported to have such expression pattern and function modes, which expands our understanding of the diverse functions of micronemal proteins.
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JOURNAL OF INFECTION
·
2022
·
IF 38.637
Zhuo-Er Qiu,Lei Chen,Xiao-Chun Hou,Jie Sheng,Jian-Bang Xu,Jia-Wen Xu,Dong-Dong Gao,Ze-Xin Huang,Tian-Lun Lei,Zi-Yang Huang,Lei Peng,Hai-Long Yang,Qin-Hua Lin,Yun-Xin Zhu,Wei-Jie Guan,Zhao-Rong Lun,Wen-Liang Zhou,Yi-Lin Zhang
Summary Toxoplasma gondii is a widespread parasitic protozoan causing toxoplasmosis including pulmonary toxoplasmosis. As the first line of host defense, airway epithelial cells play critical roles in orchestrating pulmonary innate immunity. However, the mechanism underlying the airway inflammation induced by the T. gondii infection remains largely unclear. This study demonstrated that after infection with T. gondii , the major anion channel located in the apical membranes of airway epithelial cells, cystic fibrosis transmembrane conductance regulator (CFTR), was degraded by the parasite-secreted cysteine proteases. The intracellular Cl − concentration ([Cl − ] i ) was consequently elevated, leading to activation of nuclear factor-κB (NF-κB) signaling via serum/glucocorticoid regulated kinase 1. Furthermore, the heightened [Cl − ] i and activated NF-κB signaling could be sustained in a positive feedback regulatory manner resulting from decreased intracellular cAMP level through NF-κB-mediated up-regulation of phosphodiesterase 4. Conversely, the sulfur-containing compound allicin conferred anti-inflammatory effects on pulmonary toxoplasmosis by decreasing [Cl − ] i via activation of CFTR. These results suggest that the intracellular Cl − dynamically modulated by T. gondii mediates sustained airway inflammation, which provides a potential therapeutic target against pulmonary toxoplasmosis.
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PLACENTA
·
2024
·
IF 3
Caiqun Huang
Introduction T oxoplasma gondii is an opportunistic intracellular parasite that is a major pathogenic factor in miscarriage, especially when it occurs early in pregnancy. We have previously demonstrated that the regulation of forkhead box transcription factor (Foxp3) is associated with abortion in early pregnancy caused by excretory-secretory antigen (ESA) of strain China 1. We aimed to reveal the underlying mechanism of miscarriage caused by ESA. Methods A TLR4 −/− pregnant mouse model was successfully constructed. Pregnant mice at gestational day 5 (G5) were injected with ESA. All animals were sacrificed on G13, pregnancy outcomes were observed, and abortion rates were calculated. Placental status observed by Hematoxylin-eosin staining; gene expression was measured by IHC; flow cytometry analysis was used to determine the number and function of regulatory T cells. In EL4 cells, real-time PCR and Western blot were used to evaluate gene expression and cytokines assay. Results In vivo studies revealed that ESA injection caused 83% abortion in pregnant mice but only 35% abortion in TLR4−/− pregnant mice. In addition, ESA attenuated the number and function of regulatory T cells, further suppressed Foxp3, FOXO1 levels, and upregulated CD127 expression. TLR4 −/− mice partially reversed this inhibitory effect on regulatory T cells. Furthermore, in vitro studies revealed that ESA inhibited TLR4/NF-κB signaling pathway expression and that TLR4 agonists significantly restored the ESA-induced decrease in Foxp3. Discussion These findings suggest that ESA suppresses Foxp3 expression by blocking TLR4/NF-κB signaling, resulting in miscarriage. More importantly, the results indicated that miscarriage caused by ESA is TLR4 dependent.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2020
·
IF 3.943
Yu-Nan Lu,Xu-Dong Zhao,Xiang Xu,Jing Piao,Fumie Aosai,Ying-Biao Li,Long-Xie Shen,Su-Yun Shi,Guang-Hua Xu,Juan Ma,Hu-Nan Piao,Xuejun Jin,Lian-Xun Piao
Toxoplasmosis is a parasitic zoonosis with the highest incidence in humans. Severe lesions due to acute toxoplasmosis have been recorded in the visceral organs including the liver, where hepatocytes and Kupffer cells are important innate immune cells. Arctigenin (AG) is a bioactive ingredient of Arctium lappa L. and increasing evidence suggests that AG exhibits anti-oxidant, anti-inflammatory and anti- Toxoplasma gondii ( T. gondii ) effects. However, the role of AG in acute liver damage induced by T. gondii infection remains unclear. In this study, we analyzed the effects of AG against T. gondii -induced liver damage by establishing an in vitro infection model using a murine liver cell line (NCTC-1469 cells) and an in vivo mouse model with acute T. gondii infection of virulent RH strain. In the current study, AG effectively attenuated hepatocytes apoptosis and inhibited the reproduction of T. gondii . The results of in vitro and in vivo studies showed that AG significantly reduced alanine aminotransferase/aspartate aminotransferase activities and lessened pathological damage of liver. Moreover, AG suppressed T. gondii -induced inducible nitric oxide synthase production. AG also attenuated liver inflammation by inhibiting T. gondii -induced activation of the high-mobility group box1/toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-κB) signaling pathway. These findings demonstrated that AG exhibited prominent hepatoprotective activities in toxoplasmic liver injury with anti-inflammatory effects by inhibiting the HMGB1/TLR4/NF-κB signaling axis. Thus, this study provides the basis for the development of new drugs to treat toxoplasmic hepatitis.
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PARASITOLOGY RESEARCH
·
2023
·Vol. 123
·期 1
·1-6
·
IF 2
Wang Bingxiang,Zhao Ningning,Sun Lingyu,Tan Qianqian,Xiao Qianqian,Chen Junpeng,Li Jinxuan,Zhang Xiao,Zhao Xiaomin
Difficulties of in vitro culture and genetic manipulation of Eimeria tenella have hindered the screening of virulence factors in this parasite. In this study, the E. tenella rhoptry protein 30 (EtROP30) was expressed in Toxoplasma gondii (RH∆Ku80-EtROP30), and its effect on the proliferation and virulence of parasites was investigated. The results revealed that the expression of EtROP30 had no impact on the invasion and egress processes. However, the RH∆Ku80-EtROP30 strain formed larger plaques compared to the RH∆Ku80, indicating that the EtROP30 expression promotes T. gondii proliferation. Furthermore, the RH∆Ku80-EtROP30 strain exhibited greater pathogenicity, resulting in earlier mortality and shorter overall survival time compared to RH∆Ku80. These results imply that EtROP30 expression facilitates parasite intracellular proliferation and virulence in mice, suggesting that EtROP30 might be a candidate virulence factor of E. tenella.
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JOURNAL OF VETERINARY MEDICAL SCIENCE
·
2024
·
IF 1.1
Nianyuan CHEN,Qingxiu CAI,Shujing WANG,Qingyang SONG,Ying XIE,Huijuan SHI,Hongmei LI,Xiaomin ZHAO,Ningning ZHAO,Xiao ZHANG
Protozoan parasites such as Eimeria tenella and Toxoplasma gondii pose significant health challenges in livestock and humans. The limited treatment options and rising drug resistance underscore the urgent need for new therapies. This study investigates myrcene, a monoterpene hydrocarbon classified for its antiprotozoal potential against E. tenella and T. gondii infections. Initially, we examined its effect on the sporulation process of E. tenella oocysts in vitro and its anti-E. tenella activity in vivo. Myrcene significantly reduced the sporulation rate of E. tenella oocysts at 3 and 4 mg/kg. In vivo experiments demonstrated that treatment with 4 mg/kg myrcene significantly reduced E. tenella load and oocyst output, as well as cecal lesion and weight loss caused by E. tenella infection, showing moderate anti-E. tenella activity, with an Anticoccidial Index (ACI) of 161.4. Furthermore, we investigated the anti-T. gondii activity of myrcene both in vitro and in vivo. In vitro studies showed that treatment with myrcene effectively inhibited the invasion rate and intracellular proliferation ability of T. gondii tachyzoite in DF-1 cells in a dose-dependent manner. In vivo administration prolonged the survival time in T. gondii-infected mice, suggesting notable protective effects. Additionally, it mitigated T. gondii-induced hepatosplenic toxicity by reducing parasite load in the liver and spleen, and ameliorating liver function as evidenced by decreased serum transaminase levels. In conclusion, the findings demonstrate promising anti-E. tenella and anti-T. gondii activity exhibited by myrcene warranting further exploration into its mechanisms and potential therapeutic applications.
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PHYTOMEDICINE
·
2022
·
IF 6.656
Yu Nan Lu,Xin Yu Shen,Jing Mei Lu,Guang Nan Jin,Hui Wen Lan,Xiang Xu,Lian Xun Piao
Background Toxoplasma gondii is an opportunistic protozoan that can infect host to cause toxoplasmosis . We have previously reported that resveratrol (RSV) has protective effects against liver damage in T. gondii infected mice. However, the effect of RSV on lung injury caused by T. gondii infection and its mechanism of action remain unclear. Purpose In this work, we studied the protective effects of RSV on lung injury caused by T. gondii infection and explored the underlying mechanism. Methods Molecular docking and localized surface plasmon resonance assay were used to detect the molecular interactions between RSV and target proteins. In vitro , the anti- T. gondii effects and potential anti-inflammatory mechanisms of RSV were investigated by quantitative competitive-PCR, RT-PCR, ELISA , Western blotting and immunofluorescence using RAW 264.7 cells infected with tachyzoites of T. gondii RH strain. In vivo , the effects of RSV on lung injury caused by T. gondii infection were assessed by observing pathological changes and the expression of inflammatory factors of lung. Results RSV inhibited T. gondii loads and T. gondii -derived heat shock protein 70 ( T.g. HSP70) expression in RAW 264.7 cells and lung tissues. Moreover, RSV interacts with T.g. HSP70 and toll-like receptor 4 (TLR4), respectively, and interferes with the interaction between T.g. HSP70 and TLR4. It also inhibited the overproduction of inducible nitric oxide synthase , TNF-α and high mobility group protein 1 (HMGB1) by down-regulating TLR4/nuclear factor kappa B (NF-κB) signaling pathway , which is consistent with the effect of TLR4 inhibitor CLI-095. In vivo , RSV improved the pathological lung damage produced by T. gondii infection, as well as decreased the number of inflammatory cells in bronchoalveolar lavage fluid and the release of HMGB1 and TNF-α. Conclusion These findings indicate that RSV can inhibit the proliferation of T. gondii and T.g. HSP70 expression both in vitro and in vivo . RSV can inhibit excessive inflammatory response by intervening T.g .HSP70 and HMGB1 mediated TLR4/NF-κB signaling pathway activation, thereby ameliorating lung injury caused by T. gondii infection. The present study provides new data that may be useful for the development of RSV as a new agent for the treatment of lung damage caused by T. gondii infection.
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Autophagy
·
2022
·
IF 13.391
Jiawen Fu,Lin Zhao,Yu Pang,Heming Chen,Hayashi Yamamoto,Yuntong Chen,Zhaoran Li,Noboru Mizushima,Honglin Jia
In apicomplexan parasites, the macroautophagy/autophagy machinery is repurposed to maintain the plastid-like organelle apicoplast. Previously, we showed that in Toxoplasma and Plasmodium, ATG12 interacts with ATG5 in a non-covalent manner, in contrast to the covalent interaction in most organisms. However, it remained unknown whether apicomplexan parasites have functional orthologs of ATG16L1, a protein that is essential for the function of the covalent ATG12–ATG5 complex in vivo in other organisms. Furthermore, the mechanism used by the autophagy machinery to maintain the apicoplast is unclear. We report that the ATG12–ATG5-ATG16L complex exists in Toxoplasma gondii (Tg). This complex is localized on isolated structures at the periphery of the apicoplast dependent on TgATG16L. Inducible depletion of TgATG12, TgATG5, or TgATG16L caused loss of the apicoplast and affected parasite growth. We found that a putative soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) protein, synaptosomal-associated protein 29 (TgSNAP29, Qbc SNARE), is required to maintain the apicoplast in T. gondii. TgSNAP29 depletion disrupted TgATG8 localization at the apicoplast. Additionally, we identified a putative ubiquitin-interacting motif-docking site (UDS) of TgATG8. Mutation of the UDS site abolished TgATG8 localization on the apicoplast but not lipidation. These findings suggest that the TgATG12–TgATG5-TgATG16L complex is required for biogenesis of the apicoplast, in which TgATG8 is translocated to the apicoplast via vesicles in a SNARE -dependent manner in T. gondii.Abbreviations: AID: auxin-inducible degron; CCD: coiled-coil domain; HFF: human foreskin fibroblast; IAA: indole-3-acetic acid; LAP: LC3-associated phagocytosis; NAA: 1-naphthaleneacetic acid; PtdIns3P: phosphatidylinositol-3-phosphate; SNARE: soluble N-ethylmaleimide sensitive factor attachment protein receptor; UDS: ubiquitin-interacting motif-docking site; UIM: ubiquitin-interacting motif.
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SENSORS
·
2023
·Vol. 23
·期 11
·5218
·
IF 3.9
Huiji Chen,Binbin Luo,Shengxi Wu,Shenghui Shi,Qin Dai,Zehua Peng,Mingfu Zhao
Simple SummaryA microfluidic biosensor based on a thin-core microfiber coated with molybdenum disulfide for immune detection ofToxoplasma gondiiwas illustrated. The detection range, limit of detection, detection sensitivity, specificity, and clinical properties of the proposed biosensor were explored.AbstractToxoplasma gondii(T. gondii) is a zoonotic parasite that is widely distributed and seriously endangers public health and human health. Therefore, accurate and effective detection ofT. gondiiis crucial. This study proposes a microfluidic biosensor using a thin-core microfiber (TCMF) coated with molybdenum disulfide (MoS2) for immune detection ofT. gondii. The single-mode fiber was fused with the thin-core fiber, and the TCMF was obtained by arc discharging and flame heating. In order to avoid interference and protect the sensing structure, the TCMF was encapsulated in the microfluidic chip. MoS2andT. gondiiantigen were modified on the surface of TCMF for the immune detection ofT. gondii. Experimental results showed that the detection range of the proposed biosensor forT. gondiimonoclonal antibody solutions was 1 pg/mL to 10 ng/mL with sensitivity of 3.358 nm/log(mg/mL); the detection of limit was calculated to be 87 fg/mL through the Langmuir model; the dissociation constant and the affinity constant were calculated to be about 5.79 × 10−13M and 1.727 × 1014M−1, respectively. The specificity and clinical characteristics of the biosensor was explored. The rabies virus, pseudorabies virus, andT. gondiiserum were used to confirm the excellent specificity and clinical characteristics of the biosensor, indicating that the proposed biosensor has great application potential in the biomedical field.Keywords:thin-core microfiber;microfluidic chip;molybdenum disulfide;optical fiber biosensor;toxoplasma gondii
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