Microorganisms
·
2025
·Vol. 13
·期 6
·1203
·
IF 4.2
Zhenhe Liu,Haolong Qiu,Yucong Jiang,Yuxi Mo,Linlin Lu,Yan Wang,Dandan Hu,Xingju Song
Toxoplasma gondii, an obligate intracellular protozoan parasite infecting nucleated cells of warm-blooded vertebrates, causes severe complications in immunocompromised hosts. Current therapies remain limited by suboptimal efficacy and toxicity, necessitating novel anti-toxoplasmic agents. Piceatannol (PIC), a natural stilbenoid, demonstrates multifaceted bioactivity including antimicrobial and anti-parasitic effects, suggesting therapeutic potential againstT. gondii. Our previous study revealed PIC’s potent anti-parasitic activity, selectively inhibitingT. gondiiproliferation and altering parasite morphology without host cytotoxicity. In this study, mechanistic analyses indicated that PIC disrupts mitochondrial integrity in tachyzoites, reducing mitochondrial membrane potential and ATP production while elevating ROS levels. Transcriptomic profiling identified significant suppression of oxidative phosphorylation-related genes, consistent with mitochondrial dysfunction. These findings establish PIC as a promising candidate targetingT. gondiithrough the mechanism of mitochondrial impairment.
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LUMINESCENCE
·
2026
·Vol. 41
·期 8
·e70583
·
IF 2.8
Wen Li,Jiating Chen,Jie Li,Qingqing Zhang,Jihong Chen,Pengfei Zhang,Fufeng Liu
Toxoplasma gondii is a globally prevalent obligate intracellular protozoan parasite that causes severe zoonotic disease. Given the limitations of conventional drug therapies, including susceptibility to drug resistance, and significant toxic side effects, this study aimed to evaluate the efficacy of photodynamic therapy (PDT) combined with the classic photosensitizer Rose Bengal in eradicating T. gondii tachyzoites, whilst elucidating its underlying mechanism of action. Experimental results demonstrate that Rose Bengal efficiently induces the generation of both Type I and Type II reactive oxygen species (ROS) under light exposure, exhibiting potent phototoxic killing effects against T. gondii . Further transcriptomic analysis revealed that this mechanism involves Rose Bengal disrupting metabolic and motility-related signaling pathways in T. gondii , thereby programmatically inducing T. gondii cell death. Both in vivo and in vitro experiments confirmed that this approach effectively eradicates T. gondii while demonstrating favorable biosafety. This study provides experimental evidence for developing novel photodynamic therapies against T. gondii , expanding the application potential of photodynamic therapy in combating parasitic infections.
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PHARMAZIE
·
2023
·
IF 1.6
Yan Weifeng,Cui Zhe,Li Wenxin,An Xin,Cheng Xu,Wang Sihong,Jin Chunmei
New anti- Toxoplasma gondii agents are in demand due to the emergence of high toxicity. Ginseng polysaccharides and saponins can be used to treat the replication of Toxoplasma gondii in an attempt to determine whether the medicinal uses of ginseng are supported by pharmacological
effects. Anti- Toxoplasma gondii activities of ginseng polysaccharides and saponins were examined in vitro and in vivo. The findings are the survival time and rate of Toxoplasma gondii infected mice after the intake of the total polysaccharides and saponins increased
compared to untreated control mice. The survival rate of mice treated with ginseng saponins was the highest at 83.3%, the phenomenon of splenomegaly of mice was decreased especially ( p < 0.05) treated with ginseng polysaccharides. Accordingly, ginseng polysaccharides and saponins
have a potential application in anti-Toxoplasma gondii treatments.
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mBio
·
2025
·
IF 4.7
Bolin Fan,Biyun Qin,Mingjun Li,Yuchao Zhu,Fuqiang Fan,Hao Xu,Lilan Xue,Yukun Chen,Ming Pan,Bang Shen
Toxoplasma gondii is an obligate intracellular pathogen that infects humans and many animals. It harbors unique secretory organelles to facilitate its parasitic lifestyle, including dense granules that secrete diverse proteins to different destinations. Yet the biological functions of these secretory proteins are mostly unknown. Here, we examined the roles of GRA1, the first dense granule protein discovered. GRA1 is secreted to the parasitophorous vacuole (PV), and its conditional depletion led to growth arrest of tachyzoites, suggesting a crucial role of GRA1 for parasite propagation during acute infection. Furthermore, GRA1 inactivation resulted in severe metabolic defects, including reduced glycolysis and tricarboxylic acid cycle activities and a drop in cellular ATP levels. GRA1 depletion also disrupted the integrity of the mitochondrion and apicoplasts. Mechanistically, disruption of GRA1 altered the structures of membranous tubules in the PV, called the intravacuolar network (IVN), which are thought to mediate the transport of molecules in and out of the parasites. Consistently, GRA1 inactivation impaired the secretion of various GRA proteins to the PV membrane (PVM) or host cells, including GRA17 that is involved in nutrient uptake from host cells. In agreement with the mislocalization of GRA proteins, mutants lacking GRA1 had a strong defect in absorbing nutrients like glucose and pantothenate from host cells. Consequently, the parasites displayed slower growth and a higher tendency to differentiate into bradyzoites. Together, these results suggest that GRA1 plays a vital role in maintaining the structural integrity of the IVN, thus contributing to the scavenging of host nutrients.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2024
·Vol. 25
·期 5
·2493
·
IF 4.9
Zhu Ying,Meng Yin,Zifu Zhu,Zheng Shang,Yanqun Pei,Jing Liu,Qun Liu
Iron is an indispensable nutrient for the survival ofToxoplasma gondii; however, excessive amounts can lead to toxicity. The parasite must overcome the host’s “nutritional immunity” barrier and compete with the host for iron. SinceT. gondiican infect most nucleated cells, it encounters increased iron stress during parasitism. This study assessed the impact of iron stress, encompassing both iron depletion and iron accumulation, on the growth ofT. gondii. Iron accumulation disrupted the redox balance ofT. gondiiwhile enhancing the parasite’s ability to adhere in high-iron environments. Conversely, iron depletion promoted the differentiation of tachyzoites into bradyzoites. Proteomic analysis further revealed proteins affected by iron depletion and identified the involvement of phosphotyrosyl phosphatase activator proteins in bradyzoite formation.Keywords:Toxoplasma gondii;iron depletion;iron accumulation;bradyzoite differentiation
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Metabolites
·
2023
·Vol. 13
·期 4
·476
·
IF 4.1
Qiong Xu,Yin-Yan Duan,Ming Pan,Qi-Wang Jin,Jian-Ping Tao,Si-Yang Huang
Due to the limited effectiveness of existing drugs for the treatment of toxoplasmosis, there is a dire need for the discovery of new therapeutic options. Artemether is an important drug for malaria and several studies have indicated that it also exhibits anti-T. gondiiactivity. However, its specific effect and mechanisms are still not clear. To elucidate its specific role and potential mechanism, we first evaluated its cytotoxicity and anti-Toxoplasmaeffect on human foreskin fibroblast cells, and then analyzed its inhibitory activity duringT. gondiiinvasion and intracellular proliferation. Finally, we examined its effect on mitochondrial membrane potential and reactive oxygen species (ROS) inT. gondii. The CC50value of artemether was found to be 866.4 μM, and IC50was 9.035 μM. It exhibited anti-T. gondiiactivity and inhibited the growth ofT. gondiiin a dose-dependent manner. We also found that the inhibition occurred primarily in intracellular proliferation, achieved by reducing the mitochondrial membrane integrity ofT. gondiiand stimulating ROS production. These findings suggest that the mechanism of artemether againstT. gondiiis related to a change in the mitochondrial membrane and the increase in ROS production, which may provide a theoretical basis for optimizing artemether derivatives and further improving their anti-Toxoplasmaefficacy.Keywords:Toxoplasma gondii;artemether;mitochondria;mechanism;in vitro
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2022
·
IF 7.088
Liping Jiang,Bo Liu,Shengjie Hou,Tiande Su,Qiyun Fan,Eman Alyafeai,Yaqin Tang,Mengqi Wu,Xiaohua Liu,Jing Li,Yu Hu,Wulan Li,Zhiwei Zheng,Yuan Liu,Jianzhang Wu
Due to numerous side effects of traditional treatments for toxoplasmosis , it is urgent to develop new anti- Toxoplasma agents with high efficiency and low toxicity. In this study, using drug-food-homologous chalcone skeleton as a leading compound, 6 series of chalcone derivatives were designed, synthesized, and almost 1/2 compounds have good anti- Toxoplasma activity in vitro . The quantitative structure-activity relationship model of the anti- Toxoplasma activity of the second batch of compounds was established by random forest method (R 2 = 0.9407). The Michael receptor in the molecular skeleton of chalcones plays an important role in improving the activity. Among these compounds, four chalcone derivatives exhibited potent anti - T. gondii activity and low cytotoxicity in vitro . Specifically, three of them ( 4a , 4c and 5e ) effectively inhibited the proliferation of Toxoplasma tachyzoites in vivo . Liver and spleen index and biochemical parameters, such as alanine aminotransferase , aspartate aminotransferase and malondialdehyde were significantly decreased by the three chalcone derivatives, suggesting that they have protective effects on the liver of mice infected with Toxoplasma tachyzoites. Overall, this article provides a series of promising compounds for the development of anti- Toxoplasma agents.
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PARASITE IMMUNOLOGY
·
2021
·Vol. 43
·期 12
·e12893
·
IF 2.28
Hui-Wen Lan,Yu-Nan Lu,Xu-Dong Zhao,Guang-Nan Jin,Jing-Mei Lu,Cheng-Hua Jin,Juan Ma,Xuejun Jin,Xiang Xu,Lian-Xun Piao
Toxoplasma gondii ( T . gondii ) is a neurotropic protozoan parasite, which can cause mental and behavioural disorders. The present study aimed to elucidate the effects and underlying molecular mechanisms of sertraline (SERT) on T . gondii -induced depression-like behaviours. In the present study, a mouse model and a microglial cell line (BV2 cells) model were established by infecting with the T . gondii RH strain. In in vivo and in vitro experiments, the underlying molecular mechanisms of SERT in inhibiting depression-like behaviours and cellular perturbations caused by T . gondii infection were investigated in the mouse brain and BV2 cells. The administration of SERT significantly ameliorated depression-like behaviours in T . gondii -infected mice. Furthermore, SERT inhibited T . gondii proliferation. Treatment with SERT significantly inhibited the activation of microglia and decreased levels of pro-inflammatory cytokines such as tumour necrosis factor-alpha, and interferon-gamma, by down-regulating tumour necrosis factor receptor 1/nuclear factor-kappa B signalling pathway, thereby ameliorating the depression-like behaviours induced by T . gondii infection. Our study provides insight into the underlying molecular mechanisms of the newly discovered role of SERT against T . gondii -induced depression-like behaviours.
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MEDICINAL CHEMISTRY RESEARCH
·
2021
·Vol. 30
·期 12
·2228-2239
·
IF 1.965
Shang Fan-Fan,Wang Mei-Yuan,Ai Jiang-Ping,Shen Qing-Kun,Guo Hong-Yan,Jin Chun-Mei,Chen Fen-Er,Quan Zhe-Shan,Jin Lili,Zhang Changhao
Nineteen mycophenolic acid (MPA) derivatives were designed and synthesized, and their anti- Toxoplasma activity evaluated for the first time. Among them, N -propylimidazole-modified compound E5 demonstrated the strongest activity, and the IC 50 against HFF-1 (Human Foreskin Fibroblasts-1) cells following infection with T. gondii is 80.9 μM (MPA-211.5 μM) and its selectivity index is 2.2 (MPA-1.2). In vivo experiments, E5 can significantly inhibit the proliferation of tachyzoites in the abdominal cavity of mice acutely infected with T. gondii (inhibition rates 46.7%), and this inhibitory effect was greater than that of spiramycin (inhibition rates 31.3%) and MPA (inhibition rates 15.9%), this indicated that E5 had significant protective effects on the host during acute Toxoplasma infection. In addition, E5 can reduce the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of infected mice, significantly increase the level of glutathione (GSH) in the liver, and significantly reduce the level of malondialdehyde (MDA), indicating that it has a hepatoprotective effect against T. gondii infection. Similarly, E5 can relieve hepatomegaly and splenomegaly induced by acute Toxoplasma infection. Spiramycin aggravated appetite loss in infected mice, while E5 did not. In summary, the results indicated that E5 has potential as a candidate anti- T. gondii drug.
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VETERINARY PARASITOLOGY
·
2022
·
IF 2.821
Ying Zhang,Long Cheng,Hongyu Qiu,Tiancong Sun,Ruipeng Deng,Haiyan Gong,Rongsheng Mi,Yan Huang,Chunren Wang,Zhaoguo Chen
Bromodomain (BRD) is a highly conserved structural module domain, found in various proteins, including chromatin-related proteins, nucleus acetyltransferases, and transcription-associated proteins. Toxoplasma gondii , a zoonotic protozoan, encodes at least 12 predicted BRD-containing proteins (BDPs). Here, we investigated the subcellular location and regulatory role of a hypothetical protein BDP that we named TgBDP5. The BRD of TgBDP5 did not contain the conserved Asn and Tyr residues required for acetyl-lysine recognition. TgBDP5 localized in the nucleus of the parasite and remained unchanged during parasite replication. Conditional ablation of TgBDP5 through an auxin-inducible degron-based knockdown strategy caused a growth defect in parasite replication. Depletion of TgBDP5 led to changes in the expression level of 179 genes, suggesting it as an important target for drugs acting against T. gondii .
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PARASITOLOGY INTERNATIONAL
·
2026
·
IF 2.1
Ying Zhang,Rongsheng Mi,Yang Hu,Zhuo Lan,Hongu Qiu,Chunren Wang,Zhaoguo Chen,Junrong Li
Bromodomains (BRDs) are protein interaction modules that exclusively recognize acetylation motifs, and are evolutionarily conserved and present in diverse nuclear proteins. Toxoplasma gondii is the causative agent of toxoplasmosis, with the tachyzoite stage driving pathogenesis through rapid invasion and replication within nucleated cells. Bromodomain-containing protein 4 (BDP4) is a conserved BRD protein across apicomplexans. To address the roles of T. gondii bromodomain-containing protein 4 (TgBDP4) in the lytic circle of T. gondii , the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 and an auxin-inducible degron-based conditional knockdown strategy were used to construct a conditional knockdown parasite line. Phenotypic analysis revealed a growth defect in parasite replication when TgBDP4 was depleted conditionally. TgBDP4 localized in the parasite's nucleus. Depletion of the TgBDP4 led to changes in the expression level of 874 genes. The loss of TgBDP4 resulted in widespread dysregulation of gene expression, highlighting its involvement in both transcriptional activation and repression. Notably, perturbation in the expression of seven APiAP2 transcription factors was accompanied by the down-regulation of specific secretory proteins, such as ROP37, ROP15, ROP30, MIC3, and MIC12. These findings suggest that TgBDP4 may be implicated in the regulatory network controlling secretory protein expression.
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Pharmaceutics
·
2021
·Vol. 13
·期 10
·1582
·
IF 6.321
Zhengqing Yu,Yujia Lu,Wandi Cao,Muhammad Tahir Aleem,Junlong Liu,Jianxun Luo,Ruofeng Yan,Lixin Xu,Xiaokai Song,Xiangrui Li
The pathogen of toxoplasmosis,Toxoplasma gondii(T. gondii), is a zoonotic protozoon that can affect the health of warm-blooded animals including humans. Up to now, an effective vaccine with completely protection is still inaccessible. In this study, the DNA vaccine encodingT. gondiihistone deacetylase SIR2 (pVAX1-SIR2) was constructed. To enhance the efficacy, chitosan and poly (d,l-lactic-co-glycolic)-acid (PLGA) were employed to design nanospheres loaded with the DNA vaccine, denoted as pVAX1-SIR2/CS and pVAX1-SIR2/PLGA nanospheres. The pVAX1-SIR2 plasmids were transfected into HEK 293-T cells, and the expression was evaluated by a laser scanning confocal microscopy. Then, the immune protections of pVAX1-SIR2 plasmid, pVAX1-SIR2/CS nanospheres, and pVAX1-SIR2/PLGA nanospheres were evaluated in a laboratory animal model. The in vivo findings indicated that pVAX1-SIR2/CS and pVAX1-SIR2/PLGA nanospheres could generate a mixed Th1/Th2 immune response, as indicated by the regulated production of antibodies and cytokines, the enhanced maturation and major histocompatibility complex (MHC) expression of dendritic cells (DCs), the induced splenocyte proliferation, and the increased percentages of CD4+and CD8+T lymphocytes. Furthermore, this enhanced immunity could obviously reduce the parasite burden in immunized animals through a lethal dose ofT. gondiiRH strain challenge. All these results propose that pVAX1-SIR2 plasmids entrapped in chitosan or PLGA nanospheres could be the promising vaccines against acuteT. gondiiinfections and deserve further investigations.Keywords:Toxoplasma gondii;histone deacetylase;SIR2;chitosan;PLGA;immune protection
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