Pumped up: reflections on PfATP6 as the target for artemisinins

Krishna, Sanjeev; Pulcini, Serena; Moore, Catherine; Teo, Beatrix Huei-Yi; Staines, Henry M.

doi:10.1016/j.tips.2013.10.007

Cited by 42 publications

(26 citation statements)

References 73 publications

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“…Much effort is still expended in the elucidation of the modes of action in both Plasmodium falciparum (38)(39)(40) and yeast (41)(42)(43). A yeast model uncovered a role of mitochondria during the action of artemisinins with an important function for the electron transport chain and subsequent damage by locally generated ROS (41).…”

Section: Resultsmentioning

confidence: 99%

Artemisinins, New Miconazole Potentiators Resulting in Increased Activity against Candida albicans Biofilms

Cremer

Lanckacker

Cools

et al. 2015

Antimicrob Agents Chemother

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cMucosal biofilm-related fungal infections are very common, and the incidence of recurrent oral and vulvovaginal candidiasis is significant. As resistance to azoles (the preferred treatment) is occurring, we aimed at identifying compounds that increase the activity of miconazole against Candida albicans biofilms. We screened 1,600 compounds of a drug-repositioning library in combination with a subinhibitory concentration of miconazole. Synergy between the best identified potentiators and miconazole was characterized by checkerboard analyses and fractional inhibitory concentration indices. Hexachlorophene, pyrvinium pamoate, and artesunate act synergistically with miconazole in affecting C. albicans biofilms. Synergy was most pronounced for artesunate and structural homologues thereof. No synergistic effect could be observed between artesunate and fluconazole, caspofungin, or amphotericin B. Our data reveal enhancement of the antibiofilm activity of miconazole by artesunate, pointing to potential combination therapy consisting of miconazole and artesunate to treat C. albicans biofilm-related infections.

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Section: Resultsmentioning

confidence: 99%

Artemisinins, New Miconazole Potentiators Resulting in Increased Activity against Candida albicans Biofilms

Cremer

Lanckacker

Cools

et al. 2015

Antimicrob Agents Chemother

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“…One target of artemisinin-type action in malarial and schistosome parasites is the sarco(endo) plasmic reticulum Ca 2+ -ATPase, which regulates calcium levels within the parasite (Jung et al, 2005;O'Neill et al, 2010;Lepore et al, 2011;Krishna et al, 2014). The swelling and fragmentation of the ger cisternae seen in the vitelline cells of F. hepatica following artemisinin treatment could be due to inhibition of pumps associated with their membranes and would severely affect the synthetic activity of the cells, in relation to their ability to produce and transfer the shell protein globules to the shell globule clusters.…”

Section: Discussionmentioning

confidence: 99%

A comparative study on the impact of two artemisinin derivatives, artemether and artesunate, on the female reproductive system of Fasciola hepatica

O'Neill

Johnston

Halferty

et al. 2015

Veterinary Parasitology

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“…A thapsigargin-like inhibition of calcium ATPase (SERCA2a) pumps or SERCA orthologues (e.g. PfATP6 in Plasmodium falciparum) by sesquiterpenic lactones has been reported 36,37 . However, we had no experimental evidence for such an acute inhibitory effect of LYC on SERCA2a.…”

Section: Discussionmentioning

confidence: 99%

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

Farah¹,

Branquinho²,

Roy³

et al. 2017

Archives of Cardiovascular Diseases Supplements

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Chagas disease is a neglected parasitic disease caused by the protozoan Trypanosoma cruzi. New antitrypanosomal options are desirable to prevent complications, including a high rate of cardiomyopathy. Recently, a natural substance, lychnopholide, has shown therapeutic potential, especially when encapsulated in biodegradable polymeric nanocapsules. However, little is known regarding possible adverse effects of lychnopholide. Here we show that repeated-dose intravenous administration of free lychnopholide (2.0 mg/kg/day) for 20 days caused cardiopathy and mortality in healthy C57BL/6 mice. Echocardiography revealed concentric left ventricular hypertrophy with preserved ejection fraction, diastolic dysfunction and chamber dilatation at end-stage. Single cardiomyocytes presented altered contractility and Ca 2+ handling, with spontaneous Ca 2+ waves in diastole. Acute in vitro lychnopholide application on cardiomyocytes from healthy mice also induced Ca 2+ handling alterations with abnormal RyR2-mediated diastolic Ca 2+ release. Strikingly, the encapsulation of lychnopholide prevented the cardiac alterations induced in vivo by the free form repeated doses. Nanocapsules alone had no adverse cardiac effects. Altogether, our data establish lychnopholide presented in nanocapsule form more firmly as a promising new drug candidate to cure Chagas disease with minimal cardiotoxicity. Our study also highlights the potential of nanotechnology not only to improve the efficacy of a drug but also to protect against its adverse effects. Chagas disease (CD) is an important neglected disease caused by an intracellular hemoflagellate protozoan parasite, Trypanosoma cruzi (T. cruzi).There are an estimated 6-7 million infected people worldwide, and the disease causes 12 500 deaths per year, mostly in Latin America (World Health Organization, Switzerland 2015). While CD is principally transmitted to humans by triatomine insects, other routes include blood transfusion or transplantation of contaminated organs, ingestion of contaminated food and congenital transmission from infected mothers to newborns. International migrations contribute to spread the disease in non-endemic areas such as North America, Europe and Western Pacific countries (World Health Organization, Switzerland 2015). CD evolves in different consecutive phases with a short acute period, characterized by patent parasitemia, followed by a chronic phase in which most infected individuals remain asymptomatic (indeterminate form). CD is also a common determinant of non-ischemic cardiomyopathy in addition to digestive complications and neurological disorders. Approximately 30% of patients infected with T. cruzi manifest cardiomyopathy characterized by severe myocarditis and multiple arrhythmias, and/or dilatation and physiological dysfunctions of hollow organs, mainly of the digestive tract, which develop progressively over the years or decades after infection [1][2][3][4] . The clinical course of CD shows great variability, and the mechanisms or determinants responsible for t...

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Pumped up: reflections on PfATP6 as the target for artemisinins

Cited by 42 publications

References 73 publications

Artemisinins, New Miconazole Potentiators Resulting in Increased Activity against Candida albicans Biofilms

Artemisinins, New Miconazole Potentiators Resulting in Increased Activity against Candida albicans Biofilms

A comparative study on the impact of two artemisinin derivatives, artemether and artesunate, on the female reproductive system of Fasciola hepatica

Biodegradable polymeric nanocapsules prevent cardiotoxicity of antitrypanosomal lychnopholide

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