Antiproliferative properties of Turmerone on Leishmania major: Modes of action confirmed by antioxidative and immunomodulatory roles
Graphical Abstract
Introduction
Leishmaniasis is a tropical disease caused by 20 distinct Leishmania species in humans and animals in more than 100 countries and territories [1], [2]. Several classical and atypical forms of leishmaniasis are present depending on the endemic locality, but three typical forms are medically important [1]. Visceral (VL, also named kala-azar), the most deadly form of parasitism if left untreated; mucocutaneous (MCL), the mutilating type, and cutaneous (CL), the most widespread form with serious public health complications in endemic regions in Africa, Americas and Asia notably in the Mediterranean countries [3]. Due to the complexity of the life cycle and existence of many species of reservoirs and vectors and presence of so many underlying risk factors; biological control is not effective [2], [4], [5]. To date, there is no affordable and efficient vaccines accessible [6] and chemotherapy is the only measure that has routinely been used to control the disease universally [7]. Unfortunately, almost all existing conventional drugs against leishmaniasis including the first-line drugs of meglumine antimoniate (Glucantime®, MA), sodium stibogluconate (Pentostam®), and second-line compounds such as amphotericin B, paromomycin, azole derivatives and many other synthetic chemicals are toxic, parenteral, and ineffective. Therefore, their use is no longer satisfactory and emergence of resistance is inevitable [8], [9].
Plant-derived materials and other natural products have widely been used in traditional medicines for the last centuries and have represented promise as valuable sources of lead molecules for developing novel alternative treatments [10], [11]. Curcumin, also named turmeric and other curcuminoids, constitute the main phytochemicals of Curcuma longa Linn, which is a perennial herb belonging to the Zingiberaceae family [12]. It is grown easily and distributed in tropical and subtropical areas [13].
Ar-Turmerone is an aromatic constituent extracted from the rhizome of C. longa. It is a major component in turmeric oil that has long been used in many countries, but most prevalently in Southeast Asia as a food additive and a medication [14]. Curcumin is a well-known medicinal component used to treat various microbial diseases [15]. Curcumin exhibits an extensive range of anti-oxidative, anti-inflammatory, anti-cancer, hepatoprotective, hypoglycemic, anti-lipoperoxidation, and anti-platelet effects [14], [16], [17].
This polyphenol compound is also present in fruits, beverages, vegetables and herbs [18]. It is directly associated with healthy life expectancy and reduced risk for various cognitive and biological degenerative chronic diseases such as neurologic, carcinogenic, atherosclerosis, coronary and aging diseases [19], [20], [21]. The in vitro effect of crude extracts of curcumin has previously been reported [22], [23], but so far, no study has been performed on the active molecule to assess the effect of Turmerone on Leishmania stages alone or along with meglumine antimoniate, as the drug of choice to treat all forms of leishmaniasis. Furthermore, the present investigation was also designed to conduct a panel of pharmacological and biological activities for Turmerone to elucidate its mechanisms of action. Such a broad range of experimental assays is exclusive and capable to clarify the potential outcome of the active metabolite of curcumin, Turmerone, on L. major stages as a model of predominant species in the Old World.
Section snippets
Chemical preparation
Meglumine antimoniate (Glucantime®; MA) was obtained from the Kerman health system (originally purchased from Sanofi-Aventis, France). Aromatic Turmerone was purchased from Sigma-Aldrich Co. Germany (Catalog No. CFN, 89231). Meglumine antimoniate and Turmerone were dissolved in sterile distilled water to prepare appropriate concentrations (6.25, 12.5, 25, and 50 μg/mL). Concentrations of 12.5 + 12.5, 25 + 25 and 50 + 50 μg/mL were also prepared for the assessment of the combinatory effect of
Docking
Molecular docking was used to predict the binding orientation of ar-Turmerone and Glucantime® to three protein targets of IL-12, iNOS and metacaspase to assess the level of affinity. The molecular interactions between ar-Turmerone and the target proteins of IL-12, iNOS and metacaspase (Fig. 1) as well as interactions between Glucantime® and the mentioned proteins (Fig. 2) were investigated (Supplementary file 1). According to docking results, ar-Turmerone and Glucantime® bind to these three
Discussion
Treatment of all forms of leishmaniasis by conventional synthetic compounds is a serious challenge worldwide [1]. As a consequence of the lack of an efficient vaccine and proper control measures, the treatment of leishmaniasis exclusively depends on effective therapeutic compounds [8].
Aromatic Turmerone is one of the major components and active molecules of curcumin [14]. This polyphenol compound possesses varying levels of valuable biological effects. Various reports indicate a diverse and
Conclusions
The present results demonstrated that Turmerone significantly inhibited the proliferation rate of L. major intra-macrophage amastigotes alone and more lethal effects in combination. The primary mechanism of action is more likely associated with the stimulation of powerful antioxidant and immunomodulatory roles in killing the organism. Additional investigations are crucial to demonstrating the Turmerone effect on this important parasite in murine infection models and subsequently as a treatment
Declarations
Ethics approval and consent to participate.
Not applicable.
Funding
This study was supported by Kerman Leishmaniasis Research Center and Vice-Chancellor for Research, Kerman University of Medical Sciences [grant number 96000512]. The funder had no role in the study design, data collection, data analysis, and manuscript preparation.
CRediT authorship contribution statement
Fahimeh Mohseni: Data curation, Methodology, Software. Iraj Sharifi: Conceptualization, Funding acquisition, Writing review&editing. Razieh Tavakoli Oliaee: Visualization, Investigation, Formal analysis, Writing review&editing. Zahra Babaei: Supervision. Mahshid Mostafavi: Software, Validation. Pooya Ghasemi Nejad Almani: Investigation, Software. Alireza Keyhani: Methodology, Software. Ehsan Salarkia: Methodology, Writing – original draft. Fatemeh Sharifi: Data Curation, Resources. Hossein
Consent for publication
Not applicable.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors would like to appreciate all of the staff of Leishmaniasis Research Center for their immense assistance in performing this research.
References (47)
Leishmaniasis: current situation and new perspectives
Comp. Immunol. Microbiol. Infect. Dis.
(2004)- et al.
Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases
Int. J. Biochem. Cell Biol.
(2009) - et al.
Antiaging effect of Curcuma longa L. essential oil on ultraviolet-irradiated skin
Microchem. J.
(2020) - et al.
Chemoprevention of Leishmaniasis: In-vitro antiparasitic activity of dibenzalacetone, a synthetic curcumin analog leads to apoptotic cell death in Leishmania donovani
Parasitol. Int.
(2018) - et al.
Evaluation of in vitro anti-leishmanial activities of curcumin and its derivatives “gallium curcumin, indium curcumin and diacetylecurcumin
Int. J. Infect. Dis.
(2012) - et al.
Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method
Methods.
(2001) - et al.
Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum
Int. J. Parasitol. Drugs Drug Resist.
(2017) - et al.
Niosomal formulation of amphotericin B alone and in combination with glucantime: In vitro and in vivo leishmanicidal effects
Biomed. Pharmacother.
(2019) - et al.
Curcumin for malaria therapy
Biochem. Biophys. Res. Commun.
(2005) - et al.
Host’s immune response in unresponsive and responsive patients with anthroponotic cutaneous leishmaniasis treated by meglumine antimoniate: A case-control study of Th1 and Th2 pathways
Int. Immunopharmacol.
(2019)
The potential role of nicotinamide on Leishmania tropica: An assessment of inhibitory effect, cytokines gene expression and arginase profiling
Int. Immunopharmacol.
Genetic mechanism for the stage-and tissue-specific regulation of steroid triggered programmed cell death in Drosophila
Dev. Biol.
Leishmaniasis worldwide and global estimates of its incidence
PLoS One
Epidemiological situation of Lyme borreliosis and diagnosis standards in Poland and Ukraine
Heal. Probl. Civiliz.
Risk factors for anthroponotic cutaneous leishmaniasis in unresponsive and responsive patients in a major focus, southeast of Iran
PLoS One
Leishmania vaccines entered in clinical trials: a review of literature
Int. J. Prev. Med.
Addressing a clinical challenge: guidelines for the diagnosis and treatment of leishmaniasis
BMC Med.
Drug resistance and treatment failure in leishmaniasis: a 21st century challenge
PLoS Negl. Trop. Dis.
Unresponsiveness to meglumine antimoniate in anthroponotic cutaneous leishmaniasis field isolates: analysis of resistance biomarkers by gene expression profiling
Trop. Med. Int. Heal.
Concise review: medicinal plants are effective against leishmaniasis
Biomed. Res. Ther.
Leishmanicidal and cytotoxic activities of Nigella sativa and its active principle, thymoquinone
Pharm. Biol.
A review on golden species of Zingiberaceae family around the world: Genus Curcuma, African
J. Agric. Res.
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