6-Trifluoromethyl-2-thiouracil possesses anti-Toxoplasma gondii effect in vitro and in vivo with low hepatotoxicity

Choi, Hwa-Jung; Yu, Seung-Taek; Lee, Kee‐In; Choi, Jong Soo; Chang, BoYoon; Kim, Sung-Yeon; Ko, Mi-Hwa; Song, Hyun-Ok; Park, Hyun

doi:10.1016/j.exppara.2014.05.002

Cited by 16 publications

(8 citation statements)

References 28 publications

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“…Also, CCR5-deficient (CCR5 −/− ) mice infected with T. gondii exhibited increased level of ALT 8 dpi compared to uninfected mice (Bonfá et al, 2014 ). Additionally, treatment with 6-trifluoromethyl-2-thiouracil (KH-0562) or pyrimethamine was found to restore the elevated level of ALT in infected mice to the normal level, which was thought to be due to the anti- T. gondii activity and subsequent inhibition of hepatotoxicity derived from T. gondii infection (Choi et al, 2014 ). Hypoxanthine and other purines are essential nutrients that the intracellular T. gondii parasite salvages from the surrogate host cell to sustain its growth and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Serum Metabolic Profiling of Oocyst-Induced Toxoplasma gondii Acute and Chronic Infections in Mice Using Mass-Spectrometry

et al. 2018

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Toxoplasma gondii is an obligate intracellular parasite causing severe diseases in immunocompromised individuals and congenitally infected neonates, such as encephalitis and chorioretinitis. This study aimed to determine whether serum metabolic profiling can (i) identify metabolites associated with oocyst-induced T. gondii infection and (ii) detect systemic metabolic differences between T. gondii-infected mice and controls. We performed the first global metabolomics analysis of mice serum challenged with 100 sporulated T. gondii Pru oocysts (Genotype II). Sera from acutely infected mice (11 days post-infection, dpi), chronically infected mice (33 dpi) and control mice were collected and analyzed using LC-MS/MS platform. Following False Discovery Rate filtering, we identified 3871 and 2825 ions in ESI+ or ESI− mode, respectively. Principal Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA) identified metabolomic profiles that clearly differentiated T. gondii-infected and -uninfected serum samples. Acute infection significantly influenced the serum metabolome. Our results identified common and uniquely perturbed metabolites and pathways. Acutely infected mice showed perturbations in metabolites associated with glycerophospholipid metabolism, biosynthesis of amino acid, and tyrosine metabolism. These findings demonstrated that acute T. gondii infection induces a global perturbation of mice serum metabolome, providing new insights into the mechanisms underlying systemic metabolic changes during early stage of T. gondii infection.

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Section: Discussionmentioning

confidence: 99%

Serum Metabolic Profiling of Oocyst-Induced Toxoplasma gondii Acute and Chronic Infections in Mice Using Mass-Spectrometry

et al. 2018

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“…Therefore, we assessed the plasma activities of ALT, AST, GSH, and MDA in T. gondi-iinfected liver homogenates to compare the efficacy of nitrofurantoin to that of pyrimethamine. Previously, we found that 6-trifluoromethyl-2-thiouracil, a potent anti-T.gondii compound, could recover ALT, AST, and MDA to normal level in T. gondii -infected mice but it could not increase the T. gondii - reduced GSH level [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

In Vitro and in Vivo Effects of Nitrofurantoin on Experimental Toxoplasmosis

Yeo¹,

Jin²,

Kim³

et al. 2016

Korean J Parasitol

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Toxoplasma gondii is an important opportunistic pathogen that causes toxoplasmosis, which has very few therapeutic treatment options. The most effective therapy is a combination of pyrimethamine and sulfadiazine; however, their utility is limited because of drug toxicity and serious side effects. For these reasons, new drugs with lower toxicity are urgently needed. In this study, the compound, (Z)-1-[(5-nitrofuran-2-yl)methyleneamino]-imidazolidine-2,4-dione (nitrofurantoin), showed anti-T. gondii effects in vitro and in vivo. In HeLa cells, the selectivity of nitrofurantoin was 2.3, which was greater than that of pyrimethamine (0.9). In T. gondii-infected female ICR mice, the inhibition rate of T. gondii growth in the peritoneal cavity was 44.7% compared to the negative control group after 4-day treatment with 100 mg/kg of nitrofurantoin. In addition, hematology indicators showed that T. gondii infection-induced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, biochemical parameters involved in liver injury, were reduced by nitrofurantoin significantly. Moreover, nitrofurantoin exerted significant effects on the index of antioxidant status, i.e., malondialdehyde (MDA) and glutathione (GSH). The nitrofurantoin-treated group inhibited the T. gondii-induced MDA levels while alleviating the decrease in GSH levels. Thus, nitrofurantoin is a potential anti-T. gondii candidate for clinical application.

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“…Unfortunately, in vivo efficacy of the tested drug was found to be significantly lower than that for pyrimethamine [51].…”

Section: Other Synthetic Compoundsmentioning

confidence: 77%

Human toxoplasmosis–Searching for novel chemotherapeutics

Antczak

Dzitko

Długońska

2016

Biomedicine & Pharmacotherapy

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6-Trifluoromethyl-2-thiouracil possesses anti-Toxoplasma gondii effect in vitro and in vivo with low hepatotoxicity

Cited by 16 publications

References 28 publications

Serum Metabolic Profiling of Oocyst-Induced Toxoplasma gondii Acute and Chronic Infections in Mice Using Mass-Spectrometry

Serum Metabolic Profiling of Oocyst-Induced Toxoplasma gondii Acute and Chronic Infections in Mice Using Mass-Spectrometry

In Vitro and in Vivo Effects of Nitrofurantoin on Experimental Toxoplasmosis

Human toxoplasmosis–Searching for novel chemotherapeutics

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