<i>In Vitro</i>
            Synergistic Effect of Amphotericin B and Allicin on Leishmania donovani and L. infantum

Corral, María Jesús; González‐Sánchez, Elena; Cuquerella, Montserrat; Alunda, José María

doi:10.1128/aac.00710-13

Cited by 35 publications

(19 citation statements)

References 29 publications

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“…1c). The IC 50 of miltefosine, standard drug used, was 14 μM against promastigotes and 4 μM against amastigotes, respectively, which correlated well with previously published results (Corral et al 2014). Cytotoxicity of mevastatin against host cells in vitro was determined using THP-1-differentiated macrophages and showed no inhibitory effect till 100 μM (Fig.…”

Section: Resultssupporting

confidence: 78%

Antileishmanial effect of mevastatin is due to interference with sterol metabolism

2015

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Visceral leishmaniasis (VL) is one of the most severe forms of leishmaniasis which is fatal if left untreated. Sterol biosynthetic pathway in Leishmania is currently being explored for its therapeutic potential. In the present study, we have evaluated the antileishmanial efficacy of mevastatin, a known inhibitor of 3-hydroxy-3-methyl glutaryl-CoA reductase (HMGR) enzyme. Mevastatin inhibited Leishmania donovani promastigotes and intracellular amastigotes with an 50% inhibitory concentration (IC50) value of 23.8 ± 4.2 and 7.5 ± 1.1 μM, respectively, without exhibiting toxicity towards host cell line. Mevastatin also inhibited recombinant L. donovani HMGR (LdHMGR) enzyme activity with an IC50 value of 42.2 ± 3.0 μM. Kinetic analysis revealed that the inhibition of recombinant LdHMGR activity by mevastatin was competitive with HMG-CoA. Mevastatin-treated parasites exhibited 66% reduction in ergosterol levels with respect to untreated parasites. Incubation of mevastatin-treated L. donovani promastigotes with ergosterol resulted in revival of cell growth, whereas cholesterol supplementation failed to cause reversal in cell death. To further prove the specificity of mevastatin for HMGR enzyme, HMGR-overexpressing parasites were used which showed almost threefold resistance to mevastatin. It also induced morphological changes in the parasite accompanied by lipid body accumulation. Hence, antileishmanial effect of mevastatin was due to the inhibition of HMGR, which eventually leads to reduction in ergosterol levels and hence parasite death. The present study may have implications in the treatment of visceral form of leishmaniasis.

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Section: Resultssupporting

confidence: 78%

Antileishmanial effect of mevastatin is due to interference with sterol metabolism

2015

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“…However, the selectivity index was >5 for GA and almost comparable to miltefosine. The sensitivity of promastigotes, amastigotes and macrophages towards miltefosine was in agreement with the previously published data (Corral et al, 2014;Calogeropoulou et al, 2008;Dube et al, 2007). Earlier studies showed that HMGR mRNA expression was markedly decreased in GA treated dyslipidemic hamsters (Maurya and Srivastava, 2011).…”

Section: Discussionsupporting

confidence: 92%

Glycyrrhizic acid attenuates growth of Leishmania donovani by depleting ergosterol levels

Dinesh

Soumya

Kumar

et al. 2017

Experimental Parasitology

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In the present study, glycyrrhizic acid (GA) the main component of Glycyrrhiza glabra was evaluated for its efficacy as antileishmanial agent and its mode of action explored. GA inhibits promastigotes and intracellular amastigotes in a dose dependent manner at an IC value of 34 ± 3.0 μM and 20 ± 4.2 μM respectively. GA was non-toxic against THP-1 macrophage host cell line. GA was found to inhibit recombinant Leishmania donovani HMG-CoA reductase (LdHMGR) enzyme at the half-maximum inhibitory concentration of 24 ± 4.3 μM indicating the sensitivity and specificity of GA towards the enzyme. However, GA could cause only 30% reduction in HMGR activity when measured in Leishmania promastigotes treated with 34 μM of GA. Interestingly western blot analysis revealed fivefold reduced HMGR expression in GLA treated promastigotes. To further study the mode of action of GA, we used transgenic parasites overexpressing LdHMGR. Results indicated that ∼2 fold resistance was exhibited by LdHMGR overexpressing promastigotes to GA with an IC value of 74 μM compared to the wild type parasite. This explained the specific binding of GA to LdHMGR enzyme. There was ∼2 fold depletion in ergosterol levels in wild type promastigotes compared to the HMGR overexpressors. This data was further validated by exogenous supplementation of GA treated cells with ergosterol and 40% reversal of growth inhibition was observed. The results obtained suggested that GA kills the parasite by affecting sterol biosynthetic pathway, especially by inhibiting the L. donovani HMGR and altering ergosterol levels. The finding from the current study shows that GA is a potential antileishmanial chemotherapeutic agent.

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“…It was however found to be noncytotoxic up to a concentration of 100 μM, when tested on differentiated THP-1 cells. Miltefosine inhibited amastigote growth with an IC 50 value of 3.4 μM which correlated with the previously reported data [21]. However, the standard drug killed the macrophage cells at an IC 50 value of 43.6 μM.…”

Section: Evaluation Of Antidepressants As Hmgr Inhibitorssupporting

confidence: 91%

3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGR) Enzyme of the Sterol Biosynthetic Pathway: A Potential Target against Visceral Leishmaniasis

Singh¹,

Babu²

2018

Leishmaniases as Re-Emerging Diseases

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Sterol biosynthetic pathway is explored for its therapeutic potential for Visceral Leish maniasis. In Leishmania, this pathway produces ergosterol which is absent in host and there fore is a promising strategy to combat proliferation of both extracellular and intracellular forms of the parasite with minimal host toxicity. The present chapter focuses on 3hydroxy 3methylglutarylCoA reductase (HMGR) enzyme which is the ratelimiting enzyme of the ergosterol biosynthesis. HMGR gene of L. donovani was biochemically and biophysically characterized for the first time. HMGR over expressing transgenic parasites were generated to evaluate its role in parasite growth and infection ability. A series of statins like atorvas tatin, simvastatin and mevastatin were evaluated for its therapeutic efficacy and mode of action elucidated. Atorvastatin and mevastatin were found to be killing both the promas tigote and amastigote forms of the parasite without exhibiting host cytotoxicity. Besides, non-statin class of molecules like resveratrol and glycyrrhizic acid were also analyzed for antileishmanial potential. Two antidepressants, ketanserin and mianserin were found to kill both L. donovani promastigotes and intracellular amastigotes with no apparent toxicity to the host cells. Since targeting of the sterol biosynthetic pathway enzymes may be useful therapeutically, the present work may have implications in treatment of Leishmaniasis.

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In Vitro Synergistic Effect of Amphotericin B and Allicin on Leishmania donovani and L. infantum

Cited by 35 publications

References 29 publications

Antileishmanial effect of mevastatin is due to interference with sterol metabolism

Antileishmanial effect of mevastatin is due to interference with sterol metabolism

Glycyrrhizic acid attenuates growth of Leishmania donovani by depleting ergosterol levels

3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGR) Enzyme of the Sterol Biosynthetic Pathway: A Potential Target against Visceral Leishmaniasis

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