Thesis defence by Thu Hang Nguyen

Title: Toxicological and immunomodulatory properties of the extract from Clerodendrum cyrtophyllum (Turz) leaves

Summary:

Clerodendrum cyrtophyllum Turcz, a plant belonging to the Lamiaceae family, is widely used in traditional medicine in Vietnam, China, India, Korea and Thailand for the treatment of certain conditions such as colds, enteritis, dyspepsia, throat inflammation, rheumatic arthritis, fever. Despite their frequent use, studies on their efficacy and safety are still limited to date. The main objective of this thesis was to provide scientific evidence of the anti-inflammatory and antioxidant efficacy and safety in support of the ethnopharmacological uses of C. cyrtophyllum as well as the underlying phytochemistry and molecular mechanisms of action of the leaf extract of C. cyrtophyllum.

In order to study the anti-inflammatory activity of C. cyrtophyllum leaf extract, several in vitro and in vivo tests were performed. The results showed that the treatment with the ethanolic extract of C. cyrtophyllum leaves (EE) protected the blood cell membrane from haemolysis and inhibited NO and TNF-α production in LPS-activated RAW264.7. Furthermore, the expression of genes related to inflammatory processes such as cox-2, pla2, c3a, cytokines (il-1ß, il-8, tnf-α), and nf-ƙb were downregulated in the presence of this extract.

Several experiments were also designed to prove the antioxidant activity of C. cyrtophyllum leaf extract. The results showed that the extract of this plant can directly scavenge free radicals and indirectly increase the activity of endogenous antioxidants, including glutathione (GSH), glutathione S-transferase (GST) and catalase (CAT). C. cyrtophyllum leaf extract also inhibited oxidative stress via up-regulation of sod and down-regulation of gstp2, hsp70 and gadd45bb. The antioxidant activity of this extract was shown to involve the Nrf2/keap1/ARE pathway.

In addition to the anti-inflammatory and antioxidant activity, the ethanolic extract of C. cyrtophyllum also protected zebrafish larvae from copper sulphate toxicity. To elucidate the protective mechanism of the extract, we used proteomics as a tool to assess its effects on protein alterations, biological processes and protein-protein interaction networks in response to CuSO₄. The results showed that treatment with ethanolic extract of C. cyrtophyllum up-regulated proteins in certain signaling pathways such as the ribosome, pyruvate metabolism and glycolysis/gluconeogenesis pathways or the regulation of copper metabolism. The up-regulation of these proteins by EE helps to restore protein synthesis and maintain normal development of zebrafish larvae.

To provide evidence for the safety of C. cyrtophyllum, we evaluated the toxicity of the ethanolic extract of the plant leaves in the zebrafish embryo. These results indicate the toxic effects of this plant on embryonic stages and provide insight into potential mechanisms of toxicity on embryonic development. Phytochemical analysis indicated that actenoside, cirsilineol and cirsilineol-4'-O-β-D-glucoside are the main compounds in the ethanolic and methanolic extracts of C. cyrtophyllum leaves. They can be considered as potential compounds for the discovery and development of drugs derived from C. cyrtophyllum.

Overall, our results provide scientific evidence to validate the ethnopharmacological use of this plant as well as guidance for further research to develop this plant as botanical medicines or plant-derived medicines for the benefit of human health.

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Hang will present the results of her PhD thesis, conducted in the Biology Department (URBE) under the supervision of Patrick Kestemont.