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Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes.

ABSTRACT: Natural products have made remarkable contributions to drug discovery and therapy. In this work we exploited various biochemical approaches to investigate the mode of action of 16-?-hydroxy-cleroda-3,13 (14)-Z-dien-15,16-olide (HDK-20), which we recently isolated from Polyalthia longifolia, on Trypanosoma brucei bloodstream trypomastigotes. HDK20 at concentrations ? EC50 (0.4??g/ml) was trypanocidal, with its effect irreversible after only a brief exposure time (<1?h). Fluorescence microscopic assessment of DNA configuration revealed severe cell cycle defects after 8?h of incubation with the compound, the equivalent of a single generation time. This was accompanied by DNA fragmentation as shown by Terminal deoxynucleotidyl transferase dUTP Nick-End Labelling (TUNEL) assays. HDK-20 also induced a fast and profound depolarisation of the parasites' mitochondrial membrane potential and depleted intracellular ATP levels of T. brucei. Overall, HDK20 showed a multi-target mechanism of action, which provides a biochemical explanation for the promising anti-trypanosomatid activity in our previous report.

SUBMITTER: Ebiloma GU

PROVIDER: S-EPMC5854603 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes.

Ebiloma Godwin U GU Katsoulis Evangelos E Igoli John O JO Gray Alexander I AI De Koning Harry P HP

Scientific reports 20180315 1

Natural products have made remarkable contributions to drug discovery and therapy. In this work we exploited various biochemical approaches to investigate the mode of action of 16-α-hydroxy-cleroda-3,13 (14)-Z-dien-15,16-olide (HDK-20), which we recently isolated from Polyalthia longifolia, on Trypanosoma brucei bloodstream trypomastigotes. HDK20 at concentrations ≥ EC<sub>50</sub> (0.4 μg/ml) was trypanocidal, with its effect irreversible after only a brief exposure time (<1 h). Fluorescence mi ...[more]

PMID: 29545637

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Project description:Chinese medicine is a complex system guided by traditional Chinese medicine (TCM) theories, which has proven to be especially effective in treating chronic and complex diseases. However, the underlying modes of action (MOA) are not always systematically investigated. Herein, a systematic study was designed to elucidate the multi-compound, multi-target and multi-pathway MOA of a Chinese medicine ,QSYQ, on myocardial infarction. Male Sprague Dawley rat model of myocardial infarction were administered QSYQ intragastrically for 7 days while the control group was not treated. The differentially expressed genes (DEGs) were identified from myocardial infarction rat model treated with QSYQ, followed by constructing a cardiovascular disease (CVD)-related multilevel compound-target-pathway network connecting main compounds to those DEGs supported by literature evidences and the pathways that are functionally enriched. Three conditions were compared with three replicates each: (1) sham, i.e. without left anterior descending coronary artery (LAD) ligation; (2) model, with LAD ligation; (3) QSYQ, with LAD ligation and treated with QSYQ intragastrically for 7 days, the dosage was 105.6 mg/kg once a day. Rats were sacrificed after 7 days of i.g. administration under 10% chloral hydrate anesthesia (300mg/kg). Three tissue samples on the border between infarct and non-infarct area were dissected from left ventricles of each group. The tissue samples were stored at -80M-bM-^DM-^C refrigerator. Total RNA was extracted using TRIZol Reagent (Invitrogen) and purified using RNeasy Mini kit (QIAGEN), following manufacturersM-bM-^@M-^Y protocols. RNA quality was evaluated using an Agilent 2100 Bioanalyzer and electrophoresis in 2% (w/v) agarose gels. Only RNA with RNA integrity numbers (RINs) greater than 7.0 and 28SrRNA/18S rRNA ratio greater than 0.7 was used for microarray analyses. Whole genome microarray analysis was performed using Affymetrix rat Genome 230 2.0 chips.

Dataset Information

Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes.

Publications

Multi-target mode of action of a Clerodane-type diterpenoid from Polyalthia longifolia targeting African trypanosomes.

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