Inhibitory Activities of Epidermal Growth Factor Receptor Tyrosine Kinase-Targeted Dihydroxyisoflavone and Trihydroxydeoxybenzoin Derivatives on
 Sarcocystis neurona
 ,
 Neospora caninum
 , and
 Cryptosporidium parvum
 Development

Gargala, Gilles; Baishanbo, A.; Favennec, Loïc; Audigier, François; Ballet, J.; Rossignol, Jean François

doi:10.1128/aac.49.11.4628-4634.2005

Cited by 33 publications

(25 citation statements)

References 39 publications

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“…NTZ and its two metabolites, tizoxanide (TZ) and tizoxanide-glucuronide (TZglu) were shown to inhibit the growth of C. parvum at concentrations lower than 10 mg/L (Theodos, 1998;Gargala, 2000;Cai, 2005). In vivo, it was subsequently found to be effective against C. parvum in suckling mice, nude mice, gerbils, rats and piglets (Theodos, 1998;Blagburn, 1998;Li, 2003;Baishanbo, 2005). TZ had only limited activity, but NTZ and TZglu strongly inhibited asexual and sexual stages, respectively (Gargala, 2000).…”

Section: Roxithromycinmentioning

confidence: 99%

Drug treatment and novel drug target againstCryptosporidium

Gargala

2008

Parasite

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Summary :Cryptosporidiosis emergence triggered the screening of many compounds for potential anti-cryptosporidial activity in which the majority were ineffective. The outbreak of cryptosporidiosis which occurred in Milwaukee in 1993 was not only the first significant emergence of Cryptosporidium spp. as a major human pathogen but also a huge waterborne outbreak thickening thousands of people from a major city in North America. Since then, outbreaks of cryptosporidiosis are regularly occurring throughout the world. New drugs against this parasite became consequently urgently needed. Among the most commonly used treatments against cryptosporidiosis are paromomycin, and azithromycin, which are partially effective. Nitazoxanide (NTZ)'s effectiveness was demonstrated in vitro, and in vivo using several animal models and finally in clinical trials. It significantly shortened the duration of diarrhea and decreased mortality in adults and in malnourished children. NTZ is not effective without an appropriate immune response. In AIDS patients, combination therapy restoring immunity along with antimicrobial treatment of Cryptosporidium infection is necessary. Recent investigations focused on the potential of molecular-based immunotherapy against this parasite. Others tested the effects of probiotic bacteria, but were unable to demonstrate eradication of C. parvum. New synthetic isoflavone derivatives demonstrated excellent activity against C. parvum in vitro and in a gerbil model of infection. Newly synthesized nitroor non nitro-thiazolide compounds, derived from NTZ, have been recently shown to be at least as effective as NTZ against C. parvum in vitro development and are promising new therapeutic agents.

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Section: Roxithromycinmentioning

confidence: 99%

Drug treatment and novel drug target againstCryptosporidium

Gargala

2008

Parasite

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“…Fixed parasites were briefly permeabilized in 0.1% Triton X-100 in PBS, and unspecific binding sites were blocked using 10% FBS in PBS. Parasites and infected cells were stained with the following primary antibodies: polyclonal anti-DGDG sera (1:25 or 1:50) (30), polyclonal rat anti-DGDG serum (1:25), polyclonal rabbit anti-IMC1 serum (1:500; a kind gift from C. Beckers, University of North Carolina) (37), polyclonal rabbit anti-GRA6 serum (1:500; a kind gift from L. D. Sibley, Washington University School of Medicine) (38), monoclonal TG19.179 anti-GRA2 antibody (1:500) (39), monoclonal TG054 anti-SAG-1 antibody (1:500) (40), monoclonal T8.4A12.1C3 anti-SRS9 antibody (previously called P36 or BSR4) (41), and polyclonal rat anti-Cryptosporidium serum (42). All antibodies were diluted in 1% FBS in PBS and detected using BODIPY or Texas Red-conjugated goat anti-mouse, anti-rabbit, or anti-rat IgG (H1L) antibodies (1:500) (Molecular Probes).…”

Section: Ifmentioning

confidence: 99%

Subcellular localization and dynamics of a digalactolipid-like epitope in Toxoplasma gondii

Botté

Saïdani

Mondragón

et al. 2008

Journal of Lipid Research

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Toxoplasma gondii is a unicellular parasite characterized by unique extracellular and intracellular membrane compartments. The lipid composition of subcellular membranes has not been determined, limiting our understanding of lipid homeostasis, control, and trafficking, a series of processes involved in pathogenesis. In addition to a mitochondrion, Toxoplasma contains a plastid called the apicoplast. The occurrence of a plastid raised the question of the presence of chloroplast galactolipids. Using three independent rabbit and rat antibodies against digalactosyldiacylglycerol (DGDG) from plant chloroplasts, we detected a class of Toxoplasma lipids harboring a digalactolipid-like epitope (DGLE). Immunolabeling characterization supports the notion that the DGLE polar head is similar to that of DGDG. Mass spectrometry analyses indicated that dihexosyl lipids having various hydrophobic moieties (ceramide, diacylglycerol, and acylalkylglycerol) might react with anti-DGDG, but we cannot exclude the possibility that more complex dihexosyl-terminated lipids might also be immunolabeled. DGLE localization was analyzed by immunofluorescence and immunoelectron microscopy and confirmed by subcellular fractionation. No immunolabeling of the apicoplast could be observed. DGLE was scattered in pellicle membrane domains in extracellular tachyzoites and was relocalized to the anterior tip of the cell upon invasion in an actin-dependent manner, providing insights on a possible role in pathogenetic processes. DGLE was detected in other Apicomplexa (i.e

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“…Finally, these experiments have validated the gerbil model of cryptosporidiosis even if the infection does not cause diarrhea and they are restricted to the drug's effect on oocyst shedding. It remains a reliable animal model that cor- relates with our efficient in vitro screening system and allowed us to test two families of effective compounds, the isoflavones (7,8) and the thiazolides (1).…”

mentioning

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Activity of Halogeno-Thiazolides against Cryptosporidium parvum in Experimentally Infected Immunosuppressed Gerbils (Meriones unguiculatus)

Gargala

Audigier

Favennec

et al. 2013

Antimicrob Agents Chemother

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cNitazoxanide and three halogeno-thiazolides, RM-4850, RM-4865, and RM-5038, were tested against Cryptosporidium parvum in experimentally infected immunosuppressed Mongolian gerbils. Daily 400-mg/kg doses of the four test drugs for 5 to 8 consecutive days produced similar reductions of oocyst shedding. Using early-infected gerbils, a shorter 4-day treatment with RM-5038 reduced oocyst shedding by 95%, compared to 47% for nitazoxanide (P ‫؍‬ 0.02), suggesting that RM-5038 is more effective than nitazoxanide under the experimental conditions used. We have previously reported the in vitro activities of several thiazolides against Cryptosporidium parvum and Sarcocystis neurona, two apicomplexan protozoa (1, 2). Recent tests of RM-5038 showed the same level of activity as its active circulating metabolite RM-4848, which, with RM-4850 and RM-4865, had exhibited the highest level of in vitro activity against C. parvum development. These compounds deserved to be tested in vivo to confirm their anticryptosporidial activity.The in vivo activities of nitazoxanide and three halogenothiazolides were studied in experimentally Cryptosporidium parvum-infected gerbils (Meriones unguiculatus). Animals weighing 30 to 40 g at the beginning of the study were individually housed in plastic cages equipped with a grill ceiling providing rodent food granules and water ad libitum. The cage was protected by another top wrapped with sterile paper in order to comply with level II contamination requirements. Animals were handled according to the technical and ethical regulations of the French Ministry of Agriculture. Gerbils were immunosuppressed by injection of dexamethasone (Qualimed, Puteaux, France) at 0.8 mg every 2 days and fed a low-protein diet (white bread) for at least 10 consecutive days before infection, and dexamethasone was administered until the end of the experiment. Prior to the start of treatment, each gerbil was inoculated by oral gavage with C. parvum oocysts. The test compounds were suspended in pure dimethyl sulfoxide (DMSO) and administered at a dose of 200 mg/kg of body weight twice daily by oral gavage in a constant volume. One to 3 days after the cessation of treatment, all of the animals were killed by deep sodium thiopental anesthesia. To assess C. parvum infection, the volume of the cecal and colonic contents collected from each sacrificed gerbil was suspended in a 10% (wt/vol) formalin solution and homogenized. The suspension was vortexed for 30 s and allowed to settle for an additional 30 s. Ten percent of the suspension was diluted in phosphate-buffered saline (PBS) and centrifuged at 1,800 ϫ g for 30 min. After washing, the pellet was resuspended in PBS and half of the oocyst-containing pellet was incubated with an oocyst-specific monoclonal antibody conjugated with fluorescein isothiocyanate (Crypt-aGlo; Waterborne, New Orleans, LA) in the dark at 37°C for 30 min. A CytoSpin was prepared for each specimen, and oocysts were counted by epifluorescence microscopy at a magnification of ϫ400. The number of oocyst...

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Inhibitory Activities of Epidermal Growth Factor Receptor Tyrosine Kinase-Targeted Dihydroxyisoflavone and Trihydroxydeoxybenzoin Derivatives on Sarcocystis neurona , Neospora caninum , and Cryptosporidium parvum Development

Cited by 33 publications

References 39 publications

Drug treatment and novel drug target againstCryptosporidium

Drug treatment and novel drug target againstCryptosporidium

Subcellular localization and dynamics of a digalactolipid-like epitope in Toxoplasma gondii

Activity of Halogeno-Thiazolides against Cryptosporidium parvum in Experimentally Infected Immunosuppressed Gerbils (Meriones unguiculatus)

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