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Iran J Parasitol: Vol Iran J Parasitol: Vol. 14, No. 2, Apr-Jun 2019, pp.258-268 Iran J Parasitol Tehran University of Medical Open access Journal at Iranian Society of Parasitology Sciences Public a tion http://ijpa.tums.ac.ir http://isp.tums.ac.ir http://tums.ac.ir Original Article Metabolomics Based Study of the Antileishmanial Activity of Xanthium strumarium Leaf Extract on Promastigotes Phases of Leishmania major by Proton NMR Spectroscopy Mohammad AHMADI 1,2, Ziba AKBARI 1, Mahbobeh ALIKHANI 1,2, Reza HAJHOSSIANI 2, Zahra ZAMANI 1, *Mohammad ARJMAND 1 1. Metabolomics Laboratory, Department of Biochemistry, Pasteur Institute of Iran, Tehran, Iran 2. Department of Biological Sciences, Payam Noor University, Tehran, Iran Received 16 Mar 2018 Abstract Accepted 20 Jul 2018 Background: Xanthium strumarium L. is extensively used as a traditional herb to treat many diseases and is also known as a source of phytochemicals. It has been used traditionally to treat trypanosomiasis, malaria fever, eczema, cancer, ulcer, fe- Keywords: ver, herpes headache, and skin lesion such as leishmaniasis. In this preliminary Xanthium Strumarium; study, nuclear magnetic resonance (NMR)-metabolomics approaches was used to Leishmania major; evaluate the inhibitory effects and metabolic alterations caused by leaf extract of X. NMR spectroscopy; strumarium on the stationary phases of promastigotes in Leishmania major. Metabolomics Methods: The promastigotes were cultured in Biochemistry Laboratory at Pasteur Institute of Iran in 2017, stationary phases were obtained from 5 to 6 day-old cul- tures and treated with different concentrations of the plant’s extract. Antileishma- 1 nial activity was assayed by MTT method and cell metabolites were extracted. H *Correspondence NMR spectroscopy was applied, and outliers were separated using multivariate sta- Email: tistical analysis. [email protected] Results: The most affected metabolic pathways in the experimental groups were limited to amino sugar and nucleotide sugar metabolism, cyanoamino acid metabo- lism, starch and sucrose metabolism, butanoate metabolism, and galactose metabo- lism. Conclusion: The ethanolic leaf extract of X. strumarium is a potent growth inhibi- tor of Leishmania major and can affect vital metabolic pathways of Leishmania pro- mastigotes. The assay provided new perspectives on the development of novel treatment strategies for leishmanial activity derived from natural products. 258 Available at: http://ijpa.tums.ac.ir Ahmadi et al.: Metabolomics Based Study of the Antileishmanial Activity of … Introduction eishmaniasis, the infection caused by their carboxylic skeletons, into xanthanolides several species of intracellular protozoa and guaianolides. STLs are believed to be the Lof the genus Leishmania, is identified as active metabolites of X. strumarium and have a neglected health problem by WHO, especial- caused considerable interest because of the ly in tropical and subtropical regions. These broad range of their biological activities. Ar- infections exist in two clinical manifestations, temisinin for the treatment of malaria, xan- visceral and cutaneous leishmaniasis (1). Cuta- thatin and xanthinosin for antitumor activity, neous leishmaniasis (CL) is the most prevalent parthenolide for treating migraine and clinical form worldwide with 0.7 to 1.3 million thapsigargin for curing prostate cancer all be- new cases each year and annually causes long to terpenoids classes (8). 20,000 infection cases in Iran alone (1, 2). Leishmania parasites undergo fluctuating en- Since 1923, the chemotherapy based on pen- vironmental conditions in their life cycle; tavalent antimonials (SbV) has been the first- promastigotes proliferate in the mildly alkaline line treatment for leishmaniasis, which is far and glucose-rich environment of the midgut from satisfactory. Alternative drugs such as of sandfly and amastigotes grow in the acidic amphotericin B (amphoB), pentamidine, and glucose- poor environment of the phago- miltefosine, and drug combinations have also lysosome of macrophages. There were signifi- been recommended (3). The first indications cant changes in parasite metabolism during of drug resistance were reported in the early these developmental stages (9). The altered 80s first in India and then in Nepal, in patients metabolic fluxes undoubtedly reflect adapta- who had relapsed (4). The toxicity and the tion to differing challenges that Leishmania high cost of the available drugs due to drug naturally confronts in its two hosts. Glycolysis resistance, teratogenicity and the need for the rather than gluconeogenesis is more important hospitalization of patients have resulted in the in promastigotes than in amastigotes. Differ- loss of drug effectiveness (5). entiation of procyclic promastigotes to infec- Therefore, due to the mentioned reasons, tive metacyclic promastigotes involves chang- there is an urgent need to develop safer and es in membrane fluidity in lipophosphoglycan more effective antileishmanial drugs with high (LPG) and glycerolipids structures (10). efficacy. Folk medicine based on natural Antimonials have a complex multifactorial plants is used by approximately 80% of the mode of action such as an inhibitory effect on world population. It contains about 25% of trypanothione reductase of the parasite, and modern medicine, widely applied in the treat- sodium stibogluconate [Sb(V)] inhibits fatty ment of anti-parasitic diseases (6). acid oxidation, glycolysis, and energy metabo- Xanthium strumarium L. (Cocklebur) is an an- lism (11). nual weed, including 25 species belonging to Metabonomics is one of the omics technol- the Asteraceae family, which grows in Iran ogies, which is regarded as one of the func- between August and September with local tional responses of biological systems to path- common name, Tough or Zardineh X. stru- ophysiological stimuli or genetic modifications marium is traditionally used to treat trypano- and is relevant to drug resistance studies (12). somiasis, malaria fever, eczema, cancer, ulcer, It is defined as a promising approach to study fever, herpes, headache and skin sores such as metabolic alterations within living samples leishmaniasis (7). The species contain a class after drug treatment (13). In fact, this ap- of plant terpenoids called Sesquiterpene lac- proach directly links the metabolic profile of tones (STLs) which are classified based on an organism to its corresponding genomic Available at: http://ijpa.tums.ac.ir 259 Iran J Parasitol: Vol. 14, No. 2, Apr-Jun 2019, pp.258-268 profile, which is widely used to find new tions was applied to calculate the number of pharmaceutical compounds (12). total polyphenols. Measurements were done in Due to the lack of effective chemotherapy, tetraplicate (14). the emergence of drug resistance and the growing interest in plant compounds for the Leishmania parasites treatment of parasitic diseases, this preliminary Amastigote forms of L. major (strain study aimed to explore the inhibitory effects MRHO/IR/75/ER) were originally isolated of X. strumarium leaf extract and compare the from infected Balb/c mice followed by trans- metabolome fingerprint alterations on station- formation into promastigote forms in RPMI ary phases of promastigotes in L. major treated 1640 medium supplemented with 10-20% with this substance. heat-inactivated fetal bovine serum(FBS), 100 µg/ml streptomycin, and 100 U/ml penicillin Materials and Methods G at 23-26 ºC (Sigma Aldrich, St. Louis, MO, USA). To perform leishmanicidal assays, Sta- Plant material tionary-phase promastigotes were obtained from 5 to 6 day-old cultures and centrifuged at Leaves of X. strumarium were collected from o August- September 2014 from around Ker- 3000 rpm for 10 min at 4 C (15). manshah City, Kermanshah Province, Iran. Voucher specimens were authenticated by Assay of leishmanicidal activity Central Herbarium of Tehran University The leishmanicidal assay was carried out (TUH) under voucher specimen number following a protocol (16). The promastigote forms, in stationary phase, were seeded at 48241. 5 27°C for 24 h at 2×10 promastigotes/well in Preparation of crude plant extracts a 96-well microplate. The stock solutions of The dried and powdered leaves of X. stru- each of the test samples (150 µg/mL) were marium (40 g) were exhaustively macerated added and serial dilution was carried out with with an alcohol-water solution (80%) at room RPMI medium. After 48 hours, promastigotes temperature for 72 hours. This mixture was viability was calculated by tetrazolium-dye filtrated and concentrated under reduced pres- (MTT) colorimetric method and absorbance sure to obtain a light-green extract. The result- was measured at 545 nm in the presence of ing extract was mixed with active charcoal, reference length wave 630 and the percentage centrifuged to isolate plant pigments and of the viability of the promastigotes was stored at -20 0C until required for bioassay. measured according to IC50. The results were expressed according to the amount of the ex- Determination of total polyphenol content tract concentration (15-0.000015 µg/mL) re- Total phenolic content was determined us- quired to reduce the absorbance to half (IC50) ing the Folin-Ciocalteau reaction (2014). The that of the negative control wells. calibration curve of gallic acid standard solu- Cell extraction for metabolite analysis Amphotericin B(0.5 mg/ml) and pro- Stationary promastigotes (initial concentra- mastigotes with no drugs were used as posi- tion 1×109 parasites/vial) were treated with tive and negative
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