scholarly journals Artemisone and Artemiside Control Acute and Reactivated Toxoplasmosis in a Murine Model

2009 ◽  
Vol 53 (10) ◽  
pp. 4450-4456 ◽  
Author(s):  
Ildiko R. Dunay ◽  
Wing Chi Chan ◽  
Richard K. Haynes ◽  
L. David Sibley
Keyword(s):  
Side Effects ◽  
Toxoplasma Gondii ◽  
Murine Model ◽  
Acute Infection ◽  
Immunocompromised Patients ◽  
Artemisinin Derivatives ◽  
Parasite Replication ◽  
Derivatives Of

ABSTRACT Immunocompromised patients are at risk of developing toxoplasmosis, and although chemotherapy is available, standard treatments are often complicated by severe side effects. Artemisinin is a new highly potent antimalarial drug that has activity against Toxoplasma gondii in vitro. However, artemisinin derivatives have previously been ineffective in vivo using a rat model of toxoplasmosis. In the present study, the efficacy of several new artemisinin derivates was investigated for treatment of mice infected with the parasite Toxoplasma gondii. Artemiside and artemisone displayed better inhibition than either artemisinin or artesunate against the parasite in vitro. Artemiside and artemisone treatment controlled parasite replication in vivo, and mice survived the acute infection. In a murine model of reactivated toxoplasmosis, both drugs increased survival, although artemiside was more effective. These results indicate that these newer derivatives of artemisinin may have potential for treatment of toxoplasmosis.

Inhibitors of Acetylcholinesterase Derived from 7-Methoxytacrine and Their Effects on the Choline Transporter CHT1

2016 ◽  
Vol 43 (1-2) ◽  
pp. 45-58 ◽  
Author(s):  
Zdenka Kristofikova ◽  
Jan Ricny ◽  
Ondrej Soukup ◽  
Jan Korabecny ◽  
Eugenie Nepovimova ◽  
...  
Keyword(s):  
Side Effects ◽  
Amyloid Β ◽  
Acetylcholinesterase Inhibitors ◽  
Side Chain ◽  
Choline Transporter ◽  
Disease Therapy ◽  
Cortical Membranes ◽  
Derivatives Of

Background: Reversible acetylcholinesterase inhibitors are used in Alzheimer disease therapy. However, tacrine and its derivatives have severe side effects. Derivatives of the tacrine analogue 7-methoxytacrine (MEOTA) are less toxic. Methods: We evaluated new derivatives of 7-MEOTA (2 homodimers linked by 2 C4-C5 chains and 5 N-alkylated C4-C8 side chain derivatives) in vitro, using the rat hippocampal choline transporter CHT1. Results: Some derivatives were effective inhibitors of rat acetylcholinesterase and comparable with 7-MEOTA. All derivatives were able to inhibit CHT1, probably via quaternary ammonium, and this interaction could be involved in the enhancement of their detrimental side effects and/or in the attenuation of their promising effects. Under conditions of disrupted lipid rafts, the unfavorable effects of some derivatives were weakened. Only tacrine was probably able to stereospecifically interact with the naturally occurring amyloid-β isoform and to simultaneously stimulate CHT1. Some derivatives, when coincubated with amyloid β, did not influence CHT1. All derivatives also increased the fluidity of the cortical membranes. Conclusion: The N-alkylated derivative of 7-MEOTA bearing from C4 side chains appears to be the most promising compound and should be evaluated in future in vivo research.

scholarly journals p47 GTPases Regulate Toxoplasma gondii Survival in Activated Macrophages

2005 ◽  
Vol 73 (6) ◽  
pp. 3278-3286 ◽  
Author(s):  
Barbara A. Butcher ◽  
Robert I. Greene ◽  
Stanley C. Henry ◽  
Kimberly L. Annecharico ◽  
J. Brice Weinberg ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Acute Infection ◽  
Host Cells ◽  
Intracellular Growth ◽  
Latex Beads ◽  
Cellular Factors ◽  
Ifn Γ ◽  
Normal Inhibition

ABSTRACT The cytokine gamma interferon (IFN-γ) is critical for resistance to Toxoplasma gondii. IFN-γ strongly activates macrophages and nonphagocytic host cells to limit intracellular growth of T. gondii; however, the cellular factors that are required for this effect are largely unknown. We have shown previously that IGTP and LRG-47, members of the IFN-γ-regulated family of p47 GTPases, are required for resistance to acute T. gondii infections in vivo. In contrast, IRG-47, another member of this family, is not required. In the present work, we addressed whether these GTPases are required for IFN-γ-induced suppression of T. gondii growth in macrophages in vitro. Bone marrow macrophages that lacked IGTP or LRG-47 displayed greatly attenuated IFN-γ-induced inhibition of T. gondii growth, while macrophages that lacked IRG-47 displayed normal inhibition. Thus, the ability of the p47 GTPases to limit acute infection in vivo correlated with their ability to suppress intracellular growth in macrophages in vitro. Using confocal microscopy and sucrose density fractionation, we demonstrated that IGTP largely colocalizes with endoplasmic reticulum markers, while LRG-47 was mainly restricted to the Golgi. Although both IGTP and LRG-47 localized to vacuoles containing latex beads, neither protein localized to vacuoles containing live T. gondii. These results suggest that IGTP and LRG-47 are able to regulate host resistance to acute T. gondii infections through their ability to inhibit parasite growth within the macrophage.

scholarly journals Antimalarial Properties of Dunnione Derivatives as NQO2 Substrates

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3697 ◽  
Author(s):  
Monivan Chhour ◽  
Agnès Aubouy ◽  
Sandra Bourgeade-Delmas ◽  
Pierre Pério ◽  
Hélène Ternet-Fontebasso ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Natural Product ◽  
Murine Model ◽  
Blood Cells ◽  
Oxygen Species ◽  
Ic50 Value ◽  
Quinone Reductases ◽  
Derivatives Of

Dunnione, a natural product isolated from the leaves of Streptocarpus dunnii (Gesneriaceae), acts as a substrate for quinone-reductases that may be associated with its antimalarial properties. Following our exploration of reactive oxygen species-producing compounds such as indolones, as possible new approaches for the research of new ways to treat this parasitosis, we explored derivatives of this natural product and their possible antiplasmodial and antimalarial properties, in vitro and in vivo, respectively. Apart from one compound, all the products tested had weak to moderate antiplasmodial activities, the best IC50 value being equal to 0.58 µM. In vivo activities in the murine model were moderate (at a dose of 50 mg/kg/mice, five times higher than the dose of chloroquine). These results encourage further pharmacomodulation steps to improve the targeting of the parasitized red blood cells and antimalarial activities.

scholarly journals Determination of lumefantrine as an effective drug against Toxoplasma gondii infection – in vitro and in vivo study

Parasitology ◽  
2020 ◽  
pp. 1-7
Author(s):  
Dawei Wang ◽  
Mengen Xing ◽  
Saeed El-Ashram ◽  
Yingying Ding ◽  
Xiao Zhang ◽  
...  
Keyword(s):  
Side Effects ◽  
Toxoplasma Gondii ◽  
Parasite Burden ◽  
Vero Cells ◽  
Negative Control ◽  
Protective Mechanism ◽  
High Dose ◽  
Mouse Tissues

Abstract Toxoplasma gondii is an obligate intracellular protozoan parasite, which can infect almost all warm-blooded animals, including humans, leading to toxoplasmosis. Currently, the effective treatment for human toxoplasmosis is the combination of sulphadiazine and pyrimethamine. However, both drugs have serious side-effects and toxicity in the host. Therefore, there is an urgent need for the discovery of new anti-T. gondii drugs with high potency and less or no side-effects. Our findings suggest that lumefantrine exerts activity against T. gondii by inhibiting its proliferation in Vero cells in vitro without being toxic to Vero cells (P ≤ 0.01). Lumefantrine prolonged mice infected with T. gondii from death for 3 days at the concentration of 50 μg L−1 than negative control (phosphate-buffered saline treated only), and reduced the parasite burden in mouse tissues in vivo (P ≤ 0.01; P ≤ 0.05). In addition, a significant increase in interferon gamma (IFN-γ) production was observed in high-dose lumefantrine-treated mice (P ≤ 0.01), whereas interleukin 10 (IL-10) and IL-4 levels increased in low-dose lumefantrine-treated mice (P ≤ 0.01). The results demonstrated that lumefantrine may be a promising agent to treat toxoplasmosis, and more experiments on the protective mechanism of lumefantrine should be undertaken in further studies.

scholarly journals Inducible Nitric Oxide Is Essential for Host Control of Persistent but Not Acute Infection with the Intracellular Pathogen Toxoplasma gondii

1997 ◽  
Vol 185 (7) ◽  
pp. 1261-1274 ◽  
Author(s):  
Tanya M. Scharton-Kersten ◽  
George Yap ◽  
Jeanne Magram ◽  
Alan Sher
Keyword(s):  
Nitric Oxide ◽  
Toxoplasma Gondii ◽  
Acute Infection ◽  
Protective Role ◽  
Major Mechanism ◽  
Reactive Nitrogen Intermediates ◽  
Ifn Γ ◽  
Inos Knockout Mice

The induction by IFN-γ of reactive nitrogen intermediates has been postulated as a major mechanism of host resistance to intracellular pathogens. To formally test this hypothesis in vivo, the course of Toxoplasma gondii infection was assessed in nitric oxide synthase (iNOS)−/− mice. As expected, macrophages from these animals displayed defective microbicidal activity against the parasite in vitro. Nevertheless, in contrast to IFN-γ−/− or IL-12 p40−/− animals, iNOSdeficient mice survived acute infection and controlled parasite growth at the site of inoculation. This early resistance was ablated by neutralization of IFN-γ or IL-12 in vivo and markedly diminished by depletion of neutrophils, demonstrating the existence of previously unappreciated NO independent mechanisms operating against the parasite during early infection. By 3-4 wk post infection, however, iNOS knockout mice did succumb to T. gondii. At that stage parasite expansion and pathology were evident in the central nervous system but not the periphery suggesting that the protective role of nitric oxide against this intracellular infection is tissue specific rather than systemic.

scholarly journals In Vitro Inhibition of Toxoplasma gondii by Four New Derivatives of Artemisinin

2006 ◽  
Vol 50 (12) ◽  
pp. 4206-4208 ◽  
Author(s):  
Lorraine Jones-Brando ◽  
John D'Angelo ◽  
Gary H. Posner ◽  
Robert Yolken
Keyword(s):  
Cell Culture ◽  
Side Effects ◽  
Toxoplasma Gondii ◽  
In Vitro Inhibition ◽  
Derivatives Of

ABSTRACT Toxoplasmosis, caused by the protozoan Toxoplasma gondii, is medically important and distributed worldwide. Currently available medications are limited in terms of efficacy and side effects. We synthesized novel, nonacetal, hydrolytically stable derivatives of artemisinin and showed that they inhibit the replication of Toxoplasma gondii in cell culture.

Analogs of marinopyrrole A show enhancement to observed in vitro potency against acute Toxoplasma gondii infection

2021 ◽  
Author(s):  
Matthew C. Martens ◽  
Yan Liu ◽  
Austin G. Sanford ◽  
Alexander I. Wallick ◽  
Rosalie C. Warner ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Acute Infection ◽  
Standard Of Care ◽  
Host Cells ◽  
Infection Model ◽  
Current Standard ◽  
Clinical Consequences ◽  
Toxoplasma Gondii Infection

The apicomplexan parasite Toxoplasma gondii is the causative agent of toxoplasmosis, a globally distributed infection with severe clinical consequences for immunocompromised individuals and developing fetuses. There are few available treatments, and these are associated with potentially severe adverse effects. Marinopyrrole A, a compound discovered in a marine Streptomyces species, has previously been found to exhibit potent antimicrobial activity, prompting our interest in exploring efficacy against Toxoplasma gondii . We found that marinopyrrole A was a highly potent anti- Toxoplasma molecule, with an in vitro 50% maximal inhibitory concentration (IC 50 ) of 0.31 μM corresponding to a higher potency than that of the current standard of care (pyrimethamine); however, addition of 20% serum led to abrogation of potency, and toxicity to human cell lines was observed. Yet, application of marinopyrrole A to an in vivo lethal acute infection model facilitated significantly enhanced survival at doses of 5, 10, and 20 mg/kg. We then tested a series of marinopyrrole A analogs—RL002, RL003, and RL125—demonstrating significantly increased potency in vitro , with IC 50 values ranging from 0.09-0.17 μM (3.6-6.8X increase relative to pyrimethamine). No detectable cytotoxicity was observed up to 50 μM in human foreskin fibroblasts, with cytotoxicity in HepG2 cells ranging from ∼28-50 μM, corresponding to >200X selectivity for parasites over host cells. All analogs additionally showed reduced sensitivity to serum. Further, RL003 potently inhibited in vitro -generated bradyzoites at 0.245 μM. Taken together, these data support further development of marinopyrrole A analogs as promising anti- Toxoplasma molecules to further combat this prevalent infection.

scholarly journals Anti- Toxoplasma gondii effect of Lumefantrine in vitro and in vivo

2020 ◽  
Author(s):  
Dawei Wang ◽  
Mengen Xing ◽  
Saeed El-Ashram ◽  
Yingying Ding ◽  
Xiaoyu Sang ◽  
...  
Keyword(s):  
Side Effects ◽  
Toxoplasma Gondii ◽  
Mtt Assay ◽  
Vero Cells ◽  
Protective Mechanism ◽  
High Dose ◽  
Mouse Tissues ◽  
Ifn Γ

Abstract Background: Toxoplasma gondii is an obligate intracellular protozoan parasite, which can infect almost all warm-blooded animals, including humans, leading to toxoplasmosis. Currently, the effective treatment for human toxoplasmosis is the combination of sulfadiazine and pyrimethamine. However, both drugs have serious side effects and toxicity in the host. Therefore, there is an urgent need for the discovery of new anti-Toxoplasma drugs with high potency and less or no side-effects. Methods: The cytotoxicity of sulfadiazine and lumefantrine to Vero cells was evaluated by the methyl thiazolyl tetrazolium (MTT) assay. And MTT assay was also used to detect the inhibitory effects of lumefantrine on parasites invasion and proliferation. Flow cytometry was conducted to further verify parasites proliferation. qPCR was performed to evaluate the parasite load in the mice after lumefantrine treatment. In order to determine whether lumefantrine treatment enhances Th1 or Th2 cytokine response, IFN-γ, IL-4, and IL-10 levels in the serum of mice were determined. Results: Our findings suggest that lumefantrine exerts activity against T. gondii by inhibiting its replication and invasion of Vero cells in vitro without being toxic to the cells. Furthermore, lumefantrine protected mice with acute toxoplasmosis from death to a certain extent and reduced the parasite burden in mouse tissues in vivo. In addition, a significant increase in IFN-γ production was observed in high dose lumefantrine-treated mice while IL-10 and IL-4 levels increased in low dose lumefantrine-treated mice. Conclusions: The results of this study demonstrated that lumefantrine may be a promising agent to treat toxoplamosis, and more experiments on the protective mechanism of lumefantrine should be undertaken in further studies.Key words: Toxoplasma gondii, Lumefantrine, anti-Toxoplasma gondii, Invasion, Proliferation

scholarly journals In vitro selection implicates ROP1 as a resistance gene for an experimental therapeutic benzoquinone acyl hydrazone in Toxoplasma gondii

2020 ◽  
Author(s):  
Matthew C. Martens ◽  
Madalyn M. Won ◽  
Harim I. Won ◽  
Thomas T. Schulze ◽  
Abigail K. Judge ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Resistance Gene ◽  
In Vitro Selection ◽  
Acute Infection ◽  
Chemical Mutagenesis ◽  
Gene Encoding ◽  
Acyl Hydrazone ◽  
Globally Distributed

Toxoplasma gondii is a globally distributed apicomplexan parasite and the causative agent of toxoplasmosis in humans. While pharmaceuticals exist to combat acute infection, they can produce serious adverse reactions, demonstrating a need for enhanced therapies. KG8 is a benzoquinone acyl hydrazone chemotype identified from a previous chemical screen for which we previously showed in vitro and in vivo efficacy against T. gondii. However, the genetic target and mechanism of action of KG8 remain unknown. To investigate potential targets, we generated resistant T. gondii lines by chemical mutagenesis followed by in vitro selection. Whole genome sequencing of resistant clones revealed a P207S mutation in the gene encoding rhoptry organelle protein 1 (ROP1), in addition to two lesser resistance-conferring mutations in the genes for rhoptry organelle protein 8 (ROP8) and a putative ADP/ATP carrier protein (TGGT1_237700). Expressing ROP1P207S in parental parasites was sufficient to confer significant (10.3-fold increased EC50) KG8 resistance. After generating a library of mutants carrying hypermutated rop1 alleles followed by KG8 pressure, we sequenced the most resistant clonal isolate (>16.9-fold increased EC50) and found independent recapitulation of the P207S mutation, along with three additional mutations in the same region. We also demonstrate that a rop1 knockout strain is insensitive to KG8. These data implicate ROP1 as a putative resistance gene of KG8. This work further identifies a compound which can be used in future studies to better understand ROP1 function and highlights this novel chemotype as a potential scaffold for the development of improved T. gondii therapeutics.

scholarly journals Artemisinin-Resistant Mutants of Toxoplasma gondii Have Altered Calcium Homeostasis

2007 ◽  
Vol 51 (11) ◽  
pp. 3816-3823 ◽  
Author(s):  
Kisaburo Nagamune ◽  
Silvia N. J. Moreno ◽  
L. David Sibley
Keyword(s):  
Toxoplasma Gondii ◽  
Mechanism Of Action ◽  
Calcium Homeostasis ◽  
Apicomplexan Parasites ◽  
Calcium Dependent ◽  
Molecular Alterations ◽  
Derivatives Of ◽  
Important Drug

ABSTRACT Artemisinin is a plant sesquiterpene lactone that has become an important drug for combating malaria, especially in regions where resistance to other drugs is widespread. While the mechanism of action is debated, artemisinin has been reported to inhibit the sarcoplasmic endoplasmic reticulum Ca2+ ATPase (SERCA) in the malaria parasite. Artemisinin is also effective against Toxoplasma in vitro and in vivo, although it is less potent and, hence, is generally not used therapeutically to treat toxoplasmosis. To explore the mechanism of action, we generated chemically derived mutants of Toxoplasma gondii that were resistant to growth inhibition by this compound in vitro. Three artemisinin-resistant (ARTr) mutant clones that differed in their sensitivities in vitro by three- to fivefold compared with that of the wild-type parasites were obtained. ARTr mutants were cross-resistant to other derivatives of artemisinin, the most potent of which was artemisone. Resistance was not due to molecular alterations or differences in the expression of SERCA or other putative targets, such as proteins that code for multidrug resistance or translationally controlled tumor protein. ARTr mutants were resistant to the induction of protein secretion from micronemes, a calcium-dependent process that is triggered by artemisinin. ARTr mutants were not cross-resistant to secretion induced by thapsigargin but were more sensitive and were unable to regulate cytoslic calcium following treatment with this compound. These studies implicate calcium homeostasis in the mechanism of action of artemisinins against apicomplexan parasites.

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