The leishmanicidal activity of oleuropein is selectively regulated through inflammation- and oxidative stress-related genes

Abstract

BackgroundMuch research effort has been focused on investigating new compounds derived from low-cost sources, such as natural products, for treating leishmaniasis. Oleuropein derived from numerous plants, particularly from the olive tree, Olea europaea L. (Oleaceae), is a biophenol with many biological activities. Our previous findings showed that oleuropein exhibits leishmanicidal effects against three Leishmania spp. in vitro, and minimizes the parasite burden in L. donovani-infected BALB/c mice. The aim of the present study is to investigate the possible mechanism(s) that mediate this leishmanicidal activity.MethodsWe determined the efficacy of oleuropein in elevating ROS and NO production in L. donovani-infected J774A.1 macrophages and in explanted splenocytes and hepatocytes obtained from L. donovani-infected BALB/c mice. We also assessed the expression of genes that are related to inflammation, T-cell polarization and antioxidant defense, in splenocytes. Finally, we determined the ratios of specific IgG2a/IgG1 antibodies and DTH reactions in L. donovani-infected BALB/c mice treated with oleuropein.ResultsOleuropein was able to elevate ROS production in both in vitro and in vivo models of visceral leishmaniasis and raised NO production in ex vivo cultures of splenocytes and hepatocytes. The extensive oxidative stress found in oleuropein-treated mice was obviated by the upregulation of the host’s antioxidant enzyme (mGCLC) and the simultaneous downregulation of the corresponding enzyme of the parasite (LdGCLC). Moreover, oleuropein was able to mount a significant Th1 polarization characterized by the expression of immune genes (IL-12β, IL-10, TGF-β1, IFN-γ) and transcription factors (Tbx21 and GATA3). Moreover, this immunomodulatory effect was also correlated with an inhibitory effect on IL-1β gene expression, rather than with the expression of IL-1α, IL-1rn and TNF-α. Furthermore, oleuropein-treated BALB/c mice mounted a delayed-type hypersensitivity (DTH) response and an elevated Leishmania-specific IgG2a/IgG1 ratio that clearly demonstrated an in vivo protective mechanism.ConclusionThe ability of Oleuropein to promote a Th1 type immune response in L. donovani-infected BALB/c mice points towards the candidacy of this bioactive compound as an immunomodulatory agent that may complement therapeutic approaches to leishmaniasis.

Ethnopharmacological survey of medicinal plants in Albaha Region, Saudi Arabia

“…At present, leishmaniasis is common in the human population in different localities, including the Eastern and Southern Province of Saudi Arabia and in particular endemic in the Al-Hassa Oasis. [ 26 ] While the antileishmanial activity of Myrtus communis , Achillea biebersteinii , Olea europaea , and Dodonaea viscosa was proved,[ 27 28 29 30 31 ] further antileishmanial screening should be done in the future for the following plants Commiphora gileadensis and Dorstenia foetida .…”

Host-Directed Drug Therapies for Neglected Tropical Diseases Caused by Protozoan Parasites

“…This natural bioactive compound was shown to promote Th1 type immune responses and increase the oxidative stress within the host, both important for protection against Leishmania infection. Balb/c mice infected with L. donovani and subsequently treated with oleuropein showed a Th1 polarization characterized by expression of genes like TGF-β1 and IFN-γ as well as transcription factors like GATA3 ( Kyriazis et al, 2016 ). This immunomodulatory effect was believed to be due to the inhibition of IL-1β which promotes disease progression and non-healing phenotypes in Leishmania major infections ( Voronov et al, 2010 ; Charmoy et al, 2016 ).…”

“…This immunomodulatory effect was believed to be due to the inhibition of IL-1β which promotes disease progression and non-healing phenotypes in Leishmania major infections ( Voronov et al, 2010 ; Charmoy et al, 2016 ). In addition to these properties, oleuropein treatment increased the production of ROS in both in vitro and in vivo models of L. donovani infection ( Kyriazis et al, 2016 ). Oleuropein has also been shown to inhibit extracellular signal related kinase (ERK1/2) ( Abe et al, 2011 ).…”

Leishmanicidal Potential of Hardwickiic Acid Isolated From Croton sylvaticus

“…GCL is involved in the biosynthesis of trypanothione (TSH) (Mukherjee et al, 2009;Kyriazis et al, 2016). TSH enables the parasite to avoid the deleterious effects of nitric oxide (NO) and reactive oxygen species (ROS), which are generated by the macrophages as part of the host's defense against leishmaniasis (Mukherjee et al, 2009;Kyriazis et al, 2016). An amplification or overexpression of this enzyme has also been shown to increase in vitro resistance of Leishmania to antimonials (Grondin et al, 1997).…”