scholarly journals Ethanol and Isopropanol in Concentrations Present in Hand Sanitizers Sharply Reduce Excystation of Giardia and Entamoeba and Eliminate Oral Infectivity of Giardia Cysts in Gerbils

2015 ◽  
Vol 59 (11) ◽  
pp. 6749-6754 ◽  
Author(s):  
Aparajita Chatterjee ◽  
Giulia Bandini ◽  
Edwin Motari ◽  
John Samuelson
Keyword(s):  
Giardia Duodenalis ◽  
Single Layer ◽  
Oral Route ◽  
Protozoan Parasites ◽  
Content Type ◽  
Hand Sanitizer ◽  
Amebic Dysentery ◽  
Entamoeba Invadens ◽  
Enteric Protozoan

ABSTRACTEnteric protozoan parasites, which are spread by the fecal-oral route, are important causes of diarrhea (Giardia duodenalis) and amebic dysentery (Entamoeba histolytica). Cyst walls ofGiardiaandEntamoebahave a single layer composed of fibrils of β-1,3-linked GalNAc and β-1,4-linked GlcNAc (chitin), respectively. The goal here was to determine whether hand sanitizers that contain ethanol or isopropanol as the active microbicide might reduce transmission of these parasites. We found that treatment with these alcohols with or without drying in a rotary evaporator (to model rapid evaporation of sanitizers on hands) kills 85 to 100% of cysts ofG. duodenalisand 90 to 100% of cysts ofEntamoeba invadens(a nonpathogenic model forE. histolytica), as shown by nuclear labeling with propidium iodide and failure to excystin vitro. Alcohols with or without drying collapsed the cyst walls ofGiardiabut did not collapse the cyst walls ofEntamoeba. To validate thein vitroresults, we showed that treatment with alcohols eliminated oral infection of gerbils by 1,000G. duodenaliscysts, while a commercial hand sanitizer (Purell) killedE. invadenscysts that were directly applied to the hands. These results suggest that expanded use of alcohol-based hand sanitizers might reduce the transmission ofGiardiaandEntamoeba.

scholarly journals Characterization of a Melamino Nitroheterocycle as a Potential Lead for the Treatment of Human African Trypanosomiasis

2014 ◽  
Vol 58 (10) ◽  
pp. 5747-5757 ◽  
Author(s):  
Federica Giordani ◽  
Annamaria Buschini ◽  
Alessandro Baliani ◽  
Marcel Kaiser ◽  
Reto Brun ◽  
...  
Keyword(s):  
Human African Trypanosomiasis ◽  
Micronucleus Assay ◽  
Oral Route ◽  
Drug Candidate ◽  
African Trypanosomiasis ◽  
Content Type ◽  
Pharmacokinetic Properties ◽  
Toxic Potential ◽  
Biopharmaceutical Properties

ABSTRACTThis paper reports an evaluation of a melamino nitroheterocycle, a potential lead for further development as an agent against human African trypanosomiasis (HAT). Studies on its efficacy, physicochemical and biopharmaceutical properties, and potential for toxicity are described. The compound previously had been shown to possess exceptional activity againstTrypanosoma bruceiinin vitroassays comparable to that of melarsoprol. Here, we demonstrate that the compound also was curative in the stringent acute mouse modelT. brucei rhodesienseSTIB 900 when given intraperitoneally at 40 mg/kg of body weight. Nevertheless, activity was only moderate when the oral route was used, and no cure was obtained when the compound was tested in a stage 2 rodent model of infection. Genotoxic profiling revealed that the compound induces DNA damage by a mechanism apparently independent from nitroreduction and involving the introduction of base pair substitutions (Ames test), possibly caused by oxidative damage of the DNA (comet test). No significant genotoxicity was observed at the chromosome level (micronucleus assay). The lack of suitable properties for oral and central nervous system uptake and the genotoxic liabilities prevent the progression of this melamine nitroheterocycle as a drug candidate for HAT. Further modification of the compound is required to improve the pharmacokinetic properties of the molecule and to separate the trypanocidal activity from the toxic potential.

scholarly journals Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis

2011 ◽  
Vol 56 (1) ◽  
pp. 432-445 ◽  
Author(s):  
Partha Palit ◽  
Abhijit Hazra ◽  
Arindam Maity ◽  
R. S. K. Vijayan ◽  
Prabu Manoharan ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Oral Delivery ◽  
Leishmania Donovani ◽  
Reactive Oxygen Species Generation ◽  
Oral Route ◽  
Apoptotic Pathway ◽  
Content Type ◽  
Lead Compounds

ABSTRACTNovel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects onL. donovanipromastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 μM). Of these, PP-9 and PP-10 were the most effectivein vitroand demonstrated strong efficaciesin vivothrough the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistantLeishmania donovanistrains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation, evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption ofLeishmaniapromastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential for treating visceral leishmaniasis (VL) through the oral route.

scholarly journals Glutamate Decarboxylase-Dependent Acid Resistance in Brucella spp.: Distribution and Contribution to Fitness under Extremely Acidic Conditions

2014 ◽  
Vol 81 (2) ◽  
pp. 578-586 ◽  
Author(s):  
Maria Alessandra Damiano ◽  
Daniela Bastianelli ◽  
Sascha Al Dahouk ◽  
Stephan Köhler ◽  
Axel Cloeckaert ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Glutamate Decarboxylase ◽  
Acid Resistance ◽  
Oral Route ◽  
Genome Sequences ◽  
Content Type ◽  
Resistant Phenotype ◽  
Wide Range ◽  
Acidic Conditions

ABSTRACTBrucellais an expanding genus of major zoonotic pathogens, including at least 10 genetically very close species occupying a wide range of niches from soil to wildlife, livestock, and humans. Recently, we have shown that in the new speciesBrucella microti, the glutamate decarboxylase (Gad)-dependent system (GAD system) contributes to survival at a pH of 2.5 and also to infection in mice by the oral route. In order to study the functionality of the GAD system in the genusBrucella, 47 isolates, representative of all known species and strains of this genus, and 16 strains of the closest neighbor genus,Ochrobactrum, were studied using microbiological, biochemical, and genetic approaches. In agreement with the genome sequences, the GAD system of classical species was not functional, unlike that of most strains ofBrucella ceti,Brucella pinnipedialis, and newly described species (B. microti,Brucella inopinataBO1,B. inopinata-like BO2, andBrucellasp. isolated from bullfrogs). In the presence of glutamate, these species were more acid resistantin vitrothan classical terrestrial brucellae. Expression intransof thegadlocus from representativeBrucellaspecies in theEscherichia coliMG1655 mutant strain lacking the GAD system restored the acid-resistant phenotype. The highly conserved GAD system of the newly described or atypicalBrucellaspecies may play an important role in their adaptation to acidic external and host environments. Furthermore, the GAD phenotype was shown to be a useful diagnostic tool to distinguish these latterBrucellastrains fromOchrobactrumand from classical terrestrial pathogenicBrucellaspecies, which are GAD negative.

scholarly journals Shiga Toxin Type 1a (Stx1a) Reduces the Toxicity of the More Potent Stx2aIn VivoandIn Vitro

2019 ◽  
Vol 87 (4) ◽  
Author(s):  
Courtney D. Petro ◽  
Eszter Trojnar ◽  
James Sinclair ◽  
Zhi-Mei Liu ◽  
Mark Smith ◽  
...  
Keyword(s):  
Shiga Toxin ◽  
Lethal Dose ◽  
Intraperitoneal Administration ◽  
Epidemiological Data ◽  
Vero Cells ◽  
Oral Route ◽  
Content Type ◽  
Time To Death

ABSTRACTShiga toxin (Stx)-producingEscherichia coli(STEC) causes foodborne outbreaks of bloody diarrhea. There are two major types of immunologically distinct Stxs: Stx1a and Stx2a. Stx1a is more cytotoxic to Vero cells than Stx2a, but Stx2a has a lower 50% lethal dose (LD50) in mice. Epidemiological data suggest that infections by STEC strains that produce only Stx2a progress more often to a life-threatening sequela of infection called hemolytic-uremic syndrome (HUS) than isolates that make Stx1a only or produce both Stx1a and Stx2a. In this study, we found that anE. coliO26:H11 strain that produces both Stx1a and Stx2a was virulent in streptomycin- and ciprofloxacin-treated mice and that mice were protected by administration of an anti-Stx2 antibody. However, we discovered that in the absence of ciprofloxacin, neutralization of Stx1a enhanced the virulence of the strain, a result that corroborated our previous finding that Stx1a reduces the toxicity of Stx2a by the oral route. We further found that intraperitoneal administration of the purified Stx1a B subunit delayed the mean time to death of mice intoxicated with Stx2a and reduced the cytotoxic effect of Stx2a on Vero cells. Taken together, our data suggest that Stx1a reduces both the pathogenicity of Stx2in vivoand cytotoxicityin vitro.

scholarly journals Leishmania Genome Dynamics during Environmental Adaptation Reveal Strain-Specific Differences in Gene Copy Number Variation, Karyotype Instability, and Telomeric Amplification

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Giovanni Bussotti ◽  
Evi Gouzelou ◽  
Mariana Côrtes Boité ◽  
Ihcen Kherachi ◽  
Zoubir Harrat ◽  
...  
Keyword(s):  
Environmental Change ◽  
Copy Number ◽  
Gene Copy Number ◽  
Environmental Adaptation ◽  
Gene Copy ◽  
Protozoan Parasites ◽  
Content Type ◽  
Intrinsic Factors ◽  
Genomic Adaptation

ABSTRACT Protozoan parasites of the genus Leishmania adapt to environmental change through chromosome and gene copy number variations. Only little is known about external or intrinsic factors that govern Leishmania genomic adaptation. Here, by conducting longitudinal genome analyses of 10 new Leishmania clinical isolates, we uncovered important differences in gene copy number among genetically highly related strains and revealed gain and loss of gene copies as potential drivers of long-term environmental adaptation in the field. In contrast, chromosome rather than gene amplification was associated with short-term environmental adaptation to in vitro culture. Karyotypic solutions were highly reproducible but unique for a given strain, suggesting that chromosome amplification is under positive selection and dependent on species- and strain-specific intrinsic factors. We revealed a progressive increase in read depth towards the chromosome ends for various Leishmania isolates, which may represent a nonclassical mechanism of telomere maintenance that can preserve integrity of chromosome ends during selection for fast in vitro growth. Together our data draw a complex picture of Leishmania genomic adaptation in the field and in culture, which is driven by a combination of intrinsic genetic factors that generate strain-specific phenotypic variations, which are under environmental selection and allow for fitness gain. IMPORTANCE Protozoan parasites of the genus Leishmania cause severe human and veterinary diseases worldwide, termed leishmaniases. A hallmark of Leishmania biology is its capacity to adapt to a variety of unpredictable fluctuations inside its human host, notably pharmacological interventions, thus, causing drug resistance. Here we investigated mechanisms of environmental adaptation using a comparative genomics approach by sequencing 10 new clinical isolates of the L. donovani, L. major, and L. tropica complexes that were sampled across eight distinct geographical regions. Our data provide new evidence that parasites adapt to environmental change in the field and in culture through a combination of chromosome and gene amplification that likely causes phenotypic variation and drives parasite fitness gains in response to environmental constraints. This novel form of gene expression regulation through genomic change compensates for the absence of classical transcriptional control in these early-branching eukaryotes and opens new venues for biomarker discovery.

scholarly journals Characterization of Plasmodium Atg3-Atg8 Interaction Inhibitors Identifies Novel Alternative Mechanisms of Action in Toxoplasma gondii

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Joseph M. Varberg ◽  
Kaice A. LaFavers ◽  
Gustavo Arrizabalaga ◽  
William J. Sullivan
Keyword(s):  
Toxoplasma Gondii ◽  
Drug Targets ◽  
Inhibitory Effect ◽  
Protozoan Parasites ◽  
Conjugation System ◽  
Content Type ◽  
Similar Inhibitory Effect ◽  
High Concentrations

ABSTRACT Protozoan parasites, including the apicomplexan pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis), infect millions of people worldwide and represent major human disease burdens. Despite their prevalence, therapeutic strategies to treat infections caused by these parasites remain limited and are threatened by the emergence of drug resistance, highlighting the need for the identification of novel drug targets. Recently, homologues of the core autophagy proteins, including Atg8 and Atg3, were identified in many protozoan parasites. Importantly, components of the Atg8 conjugation system that facilitate the lipidation of Atg8 are required for both canonical and parasite-specific functions and are essential for parasite viability. Structural characterization of the P. falciparum Atg3-Atg8 (PfAtg3-Atg8) interaction has led to the identification of compounds that block this interaction. Additionally, many of these compounds inhibit P. falciparum growth in vitro, demonstrating the viability of this pathway as a drug target. Given the essential role of the Atg8 lipidation pathway in Toxoplasma, we sought to determine whether three PfAtg3-Atg8 interaction inhibitors identified in the Medicines for Malaria Venture Malaria Box exerted a similar inhibitory effect in Toxoplasma. While all three inhibitors blocked Toxoplasma replication in vitro at submicromolar concentrations, they did not inhibit T. gondii Atg8 (TgAtg8) lipidation. Rather, high concentrations of two of these compounds induced TgAtg8 lipidation and fragmentation of the parasite mitochondrion, similar to the effects seen following starvation and monensin-induced autophagy. Additionally, we report that one of the PfAtg3-Atg8 interaction inhibitors induces Toxoplasma egress and provide evidence that this is mediated by an increase in intracellular calcium in response to drug treatment.

Giardia duodenalis: Biology and Pathogenesis

2021 ◽  
Author(s):  
Rodney D. Adam
Keyword(s):  
Giardia Duodenalis ◽  
Human Pathogen ◽  
Content Type ◽  
Reduced Genome ◽  
Molecular Approaches ◽  
Technological Advances ◽  
Eukaryotic Organism ◽  
The 1960S

Giardia duodenalis captured the attention of Leeuwenhoek in 1681 while he was examining his own diarrheal stool, but, ironically, it did not really gain attention as a human pathogen until the 1960s, when outbreaks were reported. Key technological advances, including in vitro cultivation, genomic and proteomic databases, and advances in microscopic and molecular approaches, have led to understand that this is a eukaryotic organism with a reduced genome rather than a truly premitochondriate eukaryote.

scholarly journals Morphological and Motility Features of the Stable Bleb-Driven Monopodial Form of Entamoeba and Its Importance in Encystation

2020 ◽  
Vol 88 (8) ◽  
Author(s):  
Deepak Krishnan ◽  
Sudip Kumar Ghosh
Keyword(s):  
Sol Gel ◽  
Leading Edge ◽  
Cell Aggregation ◽  
Time Lapse ◽  
Purine Nucleotides ◽  
Content Type ◽  
Adenosine Antagonist ◽  
Entamoeba Invadens ◽  
Directional Cell Migration

ABSTRACT Entamoeba histolytica and its reptilian counterpart and encystation model Entamoeba invadens formed a polarized monopodial morphology when treated with pentoxifylline. This morphology was propelled by retrograde flow of the cell surface resulting from a cyclic sol-gel conversion of cytoplasm and a stable bleb at the leading edge. Pentoxifylline treatment switched the unpolarized, adherent trophozoites to the nonadherent, stable bleb-driven form and altered the motility pattern from slow and random to fast, directionally persistent, and highly chemotactic. Interestingly, exogenously added adenosine produced multiple protrusions and random motility, an opposite phenotype to that of pentoxifylline. Thus, pentoxifylline, an adenosine antagonist, may be inducing the monopodial morphology by preventing lateral protrusions and restricting the leading edge to one site. The polarized form of E. invadens was aggregation competent, and time-lapse microscopy of encystation revealed its appearance during early hours, mediating the cell aggregation by directional cell migration. The addition of purine nucleotides to in vitro encystation culture prevented the formation of polarized morphology and inhibited the cell aggregation and, thus, the encystation, which further showed the importance of the polarized form in the Entamoeba life cycle. Cell polarity and motility are essential in the pathogenesis of Entamoeba parasites, and the stable bleb-driven polarized morphology of Entamoeba may also be important in invasive amoebiasis.

Formulation and Evaluation of Microbially- triggered tablets of Valdecoxib

2010 ◽  
Vol 2 (1) ◽  
Author(s):  
Surender Verma ◽  
S. Singh ◽  
D. Mishra ◽  
Atul Gupta ◽  
Rakesh Sharma
Keyword(s):  
Phosphate Buffer ◽  
Guar Gum ◽  
Oral Route ◽  
Matrix Tablets ◽  
In Vitro Dissolution ◽  
Wet Granulation ◽  
Dissolution Study ◽  
Caecal Content ◽  
Model Drug

The objective of present study was to develop colon targeted drug delivery using bacterially triggered approach through oral route. Valdecoxib (COX-2 inhibitor) was chosen as a model drug in order to target it to colon which may prove useful in inflammatory bowel disease and related disorders. Matrix tablets of Valdecoxib were prepared by wet granulation technique utilizing different ratio of Guar gum and Sodium starch glycholate. The prepared matrix tablets were evaluated for uniformity of weight, uniformity of content, hardness and in vitro dissolution study in simulated gastric and intestinal fluid (Phosphate Buffer pH-1.2, pH-6.8 and pH-7.4), followed by Dissolution study in bio-relevant dissolution media Phosphate Buffer (pH-6.8) containing rat caecal content. The results revealed that the formulated batch had released lesser quantity of drug at pH 1.2 and pH 7.4 in 2 hors whereas in biorelevent dissolution media containing rat caecal content it released significantly higher amount of drug which was also significantly higher than the dissolution media of same pH without caecal content (microflora) and it was concluded that guar gum can be used as a potential carrier for targeting drugs to colon.

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