Natural Products That Target the Arginase in Leishmania Parasites Hold Therapeutic Promise

Visceral leishmaniasis (VL) or kala-azar is a vector-borne dreaded protozoal infection that is caused by the parasite Leishmania donovani . With increases in the dramatic infection rates, present drug toxicity, resistance, and the absence of an approved vaccine, the development of new antileishmanial compounds from plant sources remains the keystone for the control of visceral leishmaniasis. In this study, we evaluated the leishmanicidal effect of thymoquinone against L. donovani with an in vitro and ex vivo model. Thymoquinone exhibited potent antipromastigote activity with IC 50 and IC 90 concentrations achieved at 6.33 ± 1.21 and 20.71 ± 2.15 μM, respectively, whereas the IC 50 and IC 90 concentrations were found to be 7.83 ± 1.65 and 27.25 ± 2.20 μM against the intramacrophagic form of amastigotes, respectively. Morphological changes in promastigotes and growth reversibility study following treatment confirmed the leishmanicidal effect of thymoquinone. Further, thymoquinone exhibited leishmanicidal activities against L. donovani promastigote through cytoplasmic shrinkage, membrane blebbing, chromatin condensation, cellular and nuclear shrinkage, and DNA fragmentation, as observed under scanning and transmission electron microscopy analyses. The antileishmanial activity was exerted via programmed cell death as proved by exposure of phosphatidylserine, DNA nicking by TUNEL assay, and loss of mitochondrial membrane potential. Thymoquinone at a concentration of 200 μM was devoid of any cytotoxic effects against mammalian macrophage cells. Thymoquinone showed strong leishmanicidal activity against L. donovani , which is mediated via an apoptosis mode of parasitic cell death, and accordingly, thymoquinone may be the source of a new lead molecule for the cure of VL.

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“… 7 Natural products from plant origin comprise a promising source of new antileishmanial drugs. 8 − 12 …”

Section: Introductionmentioning

confidence: 99%

Thymoquinone Induced Leishmanicidal Effect via Programmed Cell Death in Leishmania donovani

et al. 2022

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“…Even less is known about the function or regulation of polyamines in parasites, despite their significance in parasite biology. This is underscored by recent studies highlighting their importance as potential therapeutic targets in trypanosomatids, which include Leishmania spp., T. brucei , and Trypanosoma cruzi [ 30 , 32 , 33 , 52 , 53 , 54 ]. The polyamine pathway in T. brucei , the causative agent of African sleeping sickness, is the target of the drug D, L-α-difluoromethylornithine (DFMO, eflornithine, ornidyl), an inhibitor of ornithine decarboxylase (ODC), that has shown remarkable therapeutic efficacy in the treatment of African trypanosomiasis [ 32 , 34 , 35 , 36 , 37 ].…”

Section: Significance Of Polyaminesmentioning

confidence: 99%

“…Because polyamines are essential for Leishmania parasites and their metabolism shows significant differences to that of the mammalian host, the polyamine pathway offers several possibilities for therapeutic design. While several recent review articles have focused on the therapeutic potential of Leishmania arginase [ 52 , 54 , 79 , 80 ] and trypanothione metabolism [ 31 , 64 , 81 , 82 , 83 ], the intent of this review is to focus on ODC, ADOMETDC, and SPDSYN in Leishmania and discuss their promise as therapeutic targets.…”

Section: Significance Of Polyaminesmentioning

confidence: 99%

Polyamine Metabolism in Leishmania Parasites: A Promising Therapeutic Target

Carter¹,

Kawasaki²,

Nahata³

et al. 2022

Medical Sciences

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Parasites of the genus Leishmania cause a variety of devastating and often fatal diseases in humans and domestic animals worldwide. The need for new therapeutic strategies is urgent because no vaccine is available, and treatment options are limited due to a lack of specificity and the emergence of drug resistance. Polyamines are metabolites that play a central role in rapidly proliferating cells, and recent studies have highlighted their critical nature in Leishmania. Numerous studies using a variety of inhibitors as well as gene deletion mutants have elucidated the pathway and routes of transport, revealing unique aspects of polyamine metabolism in Leishmania parasites. These studies have also shed light on the significance of polyamines for parasite proliferation, infectivity, and host–parasite interactions. This comprehensive review article focuses on the main polyamine biosynthetic enzymes: ornithine decarboxylase, S-adenosylmethionine decarboxylase, and spermidine synthase, and it emphasizes recent discoveries that advance these enzymes as potential therapeutic targets against Leishmania parasites.

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“…However, similar compounds are still used in human and veterinary medicine for treating humans and CanL, including mainly pentavalent antimonials, allopurinol, and miltefosine. Therefore, care should be taken to reduce the risk of developing resistance [61][62][63][64]. Immunomodulators are considered one of the keys to the future of leishmaniasis treatment, and fortunately, novel therapeutic options are under investigation [59,63,[65][66][67][68].…”

Section: Recommended Treatment Optionsmentioning

confidence: 99%

“…Therefore, care should be taken to reduce the risk of developing resistance [61][62][63][64]. Immunomodulators are considered one of the keys to the future of leishmaniasis treatment, and fortunately, novel therapeutic options are under investigation [59,63,[65][66][67][68].…”

Section: Recommended Treatment Optionsmentioning

confidence: 99%

Nutritional Modulation of the Immune Response Mediated by Nucleotides in Canine Leishmaniosis

Segarra

2021

Microorganisms

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Leishmaniasis is an emerging, uncontrolled, and neglected zoonotic disease. Climate change is contributing to its ongoing global expansion. The dog is the main reservoir; hence the importance of implementing effective treatment, prevention, and control measures in this animal species to protect public health. However, although the standard treatment for canine leishmaniosis (CanL) is effective, it does not provide full parasitological clearance, and side effects and drug resistance have been described. The host’s immune system plays a key role in the establishment and evolution of leishmaniasis. Dietary nucleotides modulate the immune response and, given their reported efficacy and safety in sick and clinically healthy Leishmania-infected dogs and because they represent a sustainable option with no associated side effects or resistance, they could be included within the prevention, treatment, and control strategies for leishmaniasis. This article briefly summarizes the scientific literature on CanL management, including unresolved issues, and reviews the scientific evidence on immunomodulatory effects of dietary nucleotides in different animal species. It also proposes a CanL management algorithm, including nucleotides. It is concluded that nutritional modulation of the immune response with nucleotides can contribute to better management of leishmaniasis following a One Health approach, especially in the COVID-19 era.

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Natural Products That Target the Arginase in Leishmania Parasites Hold Therapeutic Promise

Cited by 33 publications

References 153 publications

Thymoquinone Induced Leishmanicidal Effect via Programmed Cell Death in Leishmania donovani

Thymoquinone Induced Leishmanicidal Effect via Programmed Cell Death in Leishmania donovani

Polyamine Metabolism in Leishmania Parasites: A Promising Therapeutic Target

Nutritional Modulation of the Immune Response Mediated by Nucleotides in Canine Leishmaniosis

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