1. Biochemistry and Chemical Biology
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Immunomodulatory drug discovery from herbal medicines: Insights from organ-specific activity and xenobiotic defenses

  1. Jue Shi  Is a corresponding author
  2. Jui-Hsia Weng
  3. Timothy J Mitchison  Is a corresponding author
  1. Centre for Quantitative Systems Biology, Department of Physics and Department of Biology, Hong Kong Baptist University, China
  2. Department of Systems Biology, Harvard Medical School, United States
  3. Institute of Biological Chemistry, Academia Sinica, Taiwan
Review Article
Cite this article as: eLife 2021;10:e73673 doi: 10.7554/eLife.73673
4 figures

Figures

Systemic action of plant- and fungus-derived drugs by direct and indirect mechanisms.

This figure compares the conventional view of direct, systemic action (left side) with a number of possible indirect action pathways (right side). The indirect pathways represent mechanisms by which a drug molecule that can only access the gut or liver can achieve systemic activity.

Candidate signaling cascades that mediate the action of Indigo and polysaccharides via the gut.

Innate immune cells in the lamina propria, such as macrophages (MΦ) and Dendritic cells (DCs), can continuously sample gut luminal contents, for example, indigo and polysaccharides, by extending the phagocytic processes directly into the gut lumen and also by receiving materials transcytosed out of the lumen by Microfold cells (M cells). This capacity presumably evolved to monitor the gut microbiome and allows the immune system to monitor and respond to molecules that cannot cross the gut wall. Upon activation by xenobiotics and gut microbes, macrophages and DCs upregulate cytokines and chemokines either directly via NFκB or IRF3 signaling pathway, or indirectly by activating other immune cell types in the lamina propria, such as group three innate lymphoid cells (ILC3), T helper 17 (TH17) cells and regulatory T (Treg) cells. The intestinal epithelial cells (IEC) also perform key innate immune functions with their expressions of distinct TLRs and AHR.

Colchicine and ginsenosides activate protective pathways in the liver.

Colchicine inhibits microtubule polymerization selectively in hepatocytes, leading to activation of p62/SQSTM1 and NRF2. NRF2 then induces local cytoprotective proteins as well as a novel anti-inflammatory hepatokine, a form of GDF15, which is secreted into plasma where it acts on circulating myeloid cells. Ginsenosides, which are representative of plant-derived triterpenoids, also activate NRF2 in hepatocytes and induce cytoprotective proteins. Precisely how ginsenosides activate NRF2, and whether they induce hepatokine secretion, are unknown.

Immuno-profiling of the direct and indirect actions of TCM-derived molecules.

To predict direct immunomodulatory activities of TCM-derived molecules, it is necessary to test them in a panel of assays that employ multiple immune cell types, inputs and outputs (upper triangle). To predict indirect immunomodulatory activities, one approach is to orally dose animals or humans, then collect plasma and circulating leukocytes at different time points (lower triangle). The panel of cell-based assays can be re-purposed to discover circulating protein mediators in plasma, such as hepatokines and enterokines. In parallel, flow cytometry and single-cell analysis can be used to detect circulating leukocytes that have been educated by drug exposure. TCM-induced alterations of gene expressions in the gut and liver can also be analyzed from animal tissues to elucidate organ-specific TCM activity.

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