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Herbal extracts and their active compounds as modulators of the inflammatory signaling pathways of Toll-like receptor 2 and 4


Schink,  Anne
Multiphase Chemistry, Max Planck Institute for Chemistry, Max Planck Society;

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Schink, A. (2018). Herbal extracts and their active compounds as modulators of the inflammatory signaling pathways of Toll-like receptor 2 and 4. PhD Thesis, Universität, Mainz.

Cite as: https://hdl.handle.net/21.11116/0000-0003-2F8C-C
Acute and especially chronic inflammation significantly contribute to the progression of many severe diseases, e.g. intestinal and extraintestinal inflammation, autoimmune diseases, chronic obstructive pulmonary disease (COPD), allergic asthma and many more. Toll-like receptors (TLRs) are part of the innate immune system and play a key role in inflammatory processes. Particularly the TLR4 pathway, whose myeloid differentiation primary response 88 (MyD88)-dependent signaling cascade is, among others, shared with TLR2, comprises important target molecules to mitigate immune reactions. To date, no effective orally active TLR4 antagonists are available for clinical application. Herbal extracts and their active compounds with potent TLR4 antagonistic activities would be of very high interest as opportunity for oral treatment of different inflammatory diseases.
The extensive screening of 99 herbal extracts revealed a great potential still hidden in this field of research. Among others, anti-inflammatory herbal extracts with formerly not described influences on multiple TLR signaling pathways were found, e.g. Castanea sativa leaves and Alchemilla vulgaris plant. In addition, anti-inflammatory extracts were identified, where previously only single constituents in the extracts were observed to mitigate effects on stimulated TLR2 or TLR4 signaling pathways, but not the whole complex mixtures themselves, such as Arctostaphylos uva-ursi leaves, Cinchona pubescens bark and Humulus lupulus cones, with arbutin, cinchonine and xanthohumol, respectively. Furthermore, several extracts, especially Rheum palmatum root and Arctostaphylos uva-ursi leaves, were shown to polarize pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages.
One of the most promising extracts, Cinnamomum verum (cinnamon) bark extract was fractionated and the comprised (active) compounds were identified. Cinnamomum verum extract and its active compounds trans-cinnamaldehyde and p-cymene were shown to mitigate stimulated TLR2 and TLR4 signaling pathways. In addition, formerly unknown synergistic effects between active compounds and other compounds, which do not show anti inflammatory activities by themselves, were revealed. Cinnamomum verum extract, trans-cinnamaldehyde and p cymene were generally shown to influence early TLR2 and TLR4 signaling pathway molecules in vitro, without toxic effects. Therefore, the results may contribute to the development of new oral treatment strategies for different inflammatory diseases.