<i>In vitro</i> effect of low concentrations of oltipraz on the antioxidant defence of mouse hepatocytes and <i>Schistosoma mansoni</i> worms

El-Bassiouni, E. A.; Helmy, Mai M.; Abdelhamid, M A; Shohayeb, M.A.; Ismail, Samia

doi:10.1080/09674845.2004.11732640

Cited by 5 publications

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“…This should lead to a more oxidising intracellular environment and an inability to maintain an appropriate redox potential for proper survival of the parasite. 30 The results of the present study indicate that incubation with ART causes an increase in oxidative stress, expressed as depletion of GSH and elevation of TBARS. Incubation with PZQ showed similar but milder effects in immature worms, but had a greater action in the mature stage.…”

Section: Discussionmentioning

confidence: 91%

Modulation of the antioxidant defence in different developmental stages of Schistosoma mansoni by praziquantel and artemether

El-Bassiouni¹,

Helmy²,

Saad

et al. 2007

British Journal of Biomedical Science

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Human schistosomiasis is a chronic and debilitating parasitic disease caused by parasitic trematode worms (schistosomes). Praziquantel (PZQ) is the drug of choice as it is active against all Schistosoma species, can be administered easily, has high cure and egg reduction rates, with no or only mild side effects. Rapid re-infection following treatment and the concerns about PZQ resistance has led to the search for new drugs to treat schistosomiasis. Significant progress has been made with artemisinin derivatives (e.g., artemether [ART]) that are used for chemoprophylaxis. This present study aims to look at the effects of ART and PZQ on the antioxidant defence of immature (three-week-old) and mature (six-week-old) stages of S. mansoni. The possible development of time- or concentration-dependent changes in oxidative stress is assessed by incubation with different sublethal drug concentrations (50, 75, 100 ng/mL for both ART and PZQ) and different time periods (one and three hours). The results indicated a time- and concentration-dependent depletion of glutathione (GSH), which was greater in the immature worms after incubation with ART. On addition of ART to the incubation medium of mature and immature worms, elevation in lipid peroxidation (TBARS) level was observed, which was time- and concentration-dependent, and more prominent in the immature schistosomes. Addition of PZQ to the incubation medium containing the immature schistosomes did not have a significant effect on TBARS level, except after three hours' incubation with the highest concentration used; however, a significant rise was seen in the mature worms. The PZQ had no effect on the activities of superoxide dismutase (SOD), glutathione peroxidase (tGPx, sGPx and nGPx) and glutathione transferase (GST) in mature or immature worms. While ART induced SOD activity in mature worms, it induced tGPx, nGPx and GST activities in a time- and concentration-dependent manner in both mature and immature worms. Activation was more prominent in the immature schistosomes. The results of the present study indicate that the immature schistosomes are more prone to oxidative killing, which probably participates in the mechanism of antischistosomal action of ART against the immature stage of S. mansoni. The results suggest that the mechanism of schistosomicidal action of PZQ is probably not substantially dependent on oxidative stress or oxidative killing.

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Section: Discussionmentioning

confidence: 91%

Modulation of the antioxidant defence in different developmental stages of Schistosoma mansoni by praziquantel and artemether

El-Bassiouni¹,

Helmy²,

Saad

et al. 2007

British Journal of Biomedical Science

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“…These compounds are structurally related to one of our best TcTIM inhibitors, the [1,2,4]thiadiazol-5(4H)-one 3 ( Figure 1B) [11]. On the other hand, the 3-H-1,2-dithiole heterocycle has been previously described as the framework responsible for schistosomicidal activity, e.g., in oltipraz (4, Figure 1C) [15].…”

Section: Introductionmentioning

confidence: 99%

3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

et al. 2015

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Abstract:The current pharmacological Chagas disease treatments, using Nifurtimox or Benznidazole, show limited therapeutic results and are associated with potential side effects, OPEN ACCESSMolecules 2015, 20 14596 like mutagenicity. Using random screening we have identified new chemotypes that were able to inhibit relevant targets of the Trypanosoma cruzi. We found 3H-[1,2]dithioles with the ability to inhibit Trypanosoma cruzi triosephosphate isomerase (TcTIM). Herein, we studied the structural modifications of this chemotype to analyze the influence of volume, lipophilicity and electronic properties in the anti-T. cruzi activity. Their selectivity to parasites vs. mammalian cells was also examined. To get insights into a possible mechanism of action, the inhibition of the enzymatic activity of TcTIM and cruzipain, using the isolated enzymes, and the inhibition of membrane sterol biosynthesis and excreted metabolites, using the whole parasite, were achieved. We found that this structural framework is interesting for the generation of innovative drugs for the treatment of Chagas disease.

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“…Disruption of the glutathione system is known to trigger S. mansoni death. Indeed, the anthelmintic oltipraz (OPZ; Figure 1) causes oxidative stress, decreased GSH concentration and glutathione reductase activity, and increased GPx activity [89, 90]. The drug is also known to have an effect on GST activity, although results of different studies are somewhat contradictory.…”

Section: The Glutathione Systemmentioning

confidence: 99%

“…The drug is also known to have an effect on GST activity, although results of different studies are somewhat contradictory. Treatment of worms with OPZ can produce a decrease in GST activity resulting from the non-competitive inhibition of GST activity by OPZ [89, 91] or an increase in GST activity in a concentration and time-dependant manner [90], depending on the study. Furthermore, OPZ is an inhibitor of schistosome TGR [58].…”

Section: The Glutathione Systemmentioning

confidence: 99%

The Redox Biology of Schistosome Parasites and Applications for Drug Development

Huang

Rigouin²,

Williams

2012

cpd

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Schistosomiasis caused by Schistosoma spp. is a serious public health concern, especially in subSaharan Africa. Praziquantel is the only drug currently administrated to treat this disease. However, praziquantel-resistant parasites have been identified in endemic areas and can be generated in the laboratory. Therefore, it is essential to find new therapeutics. Antioxidants are appealing drug targets. In order to survive in their hosts, schistosomes are challenged by reactive oxygen species from intrinsic and extrinsic sources. Schistosome antioxidant enzymes have been identified as essential proteins and novel drug targets and inhibition of the antioxidant response can lead to parasite death. Because the organization of the redox network in schistosomes is significantly different form that in humans, new drugs are being developed targeting schistosome antioxidants. In this paper the redox biology of schistosomes is discussed and their potential use as drug targets is reviewed. It is hoped that compounds targeting parasite antioxidant responses will become clinically relevant drugs in the near future. KeywordsSchistosoma; drug development; antioxidants; glutathione; thioredoxin; thioredoxin glutathione reductase Schistosomiasis (also known as bilharzia) is caused by blood-dwelling flatworms of the genus Schistosoma. Schistosomiasis is the second most important human parasitic disease after malaria, with an estimated 200 million people infected and greater than 200,000 deaths annually in tropical and subtropical areas [1][2][3]. Nearly 800 million people are at risk of infection in seventy-two counties [1]. In addition, schistosome infections lead to largely underreported chronic disabilities and morbidities, such as caloric malnutrition, growth stunting, anemia, and poor school performance, which lead to decreased quality of life and perpetuation of poverty [1][2][3]. The chronic morbidities associated with schistosomiasis can be exacerbated by co-infections with other helminths (parasitic worms, e.g., hookworms) [4] and schistosome infections can have significant impacts on the susceptibility and transmission of other infections, e.g., HIV [5,6] and malaria [7,8], and on immune responses to childhood vaccines [9]. Furthermore, S. haematobium is considered as a group 1 carcinogen leading to the development of urinary bladder cancer [10][11][12]. Intestinal schistosomiasis has been linked to hepatocellular carcinoma and colorectal cancer [13,14] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptFive species of Schistosoma parasitize humans including S. mansoni, S. japonicum, S. haematobium, S. intercalatum, and S. mekongi; the first three species have the widest geographic distribution whereas infections with the last two species only occur locally [15]. The life cycle of Schistosoma ssp. is complex [16,17] and is divided into sexual and asexual cycles. In the asexual cycle, eggs are released into water with feces or urine of infected individuals. Miracidia hatch from the eggs and th...

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In vitro effect of low concentrations of oltipraz on the antioxidant defence of mouse hepatocytes and Schistosoma mansoni worms

Cited by 5 publications

References 0 publications

Modulation of the antioxidant defence in different developmental stages of Schistosoma mansoni by praziquantel and artemether

Modulation of the antioxidant defence in different developmental stages of Schistosoma mansoni by praziquantel and artemether

3-H-[1,2]Dithiole as a New Anti-Trypanosoma cruzi Chemotype: Biological and Mechanism of Action Studies

The Redox Biology of Schistosome Parasites and Applications for Drug Development

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