Investigation of efficacy and safety of plant extracts and natural products on placental and immunocompetent cells

Winker, Moritz. Investigation of efficacy and safety of plant extracts and natural products on placental and immunocompetent cells. 2023, Doctoral Thesis, University of Basel, Faculty of Science.

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Drug development from natural products, such as herbal extracts and compounds, is a promising research strategy for the identification of new drug candidates. Incessant identification of new lead compounds is imperative to overcome the limitations of many modern treatment options. This holds especially true in immunological diseases, such as chronic inflammation and autoimmune disorders, as current immunosuppressive treatments come with severe side effects and efficacy loss over time. The value of natural products in this endeavour has been impressively demonstrated by compounds like cyclosporin A and tacrolimus.
To address this challenge, a multidisciplinary project was initiated. A library of 600 herbal extracts from Panama was screened for efficacy against the proliferation of lymphocytes, a hallmark feature of autoimmune diseases. An extract of Hyptis brachiata emerged as a highly effective preparation. Subsequent chemical analysis lead to the isolation and characterization of multiple constituents. The main inhibitory potential was later attributed to the antimitotic properties of the isolated aryltetralin lignans, including the well-known podophyllotoxin.
The additional weak cytokine suppression by the extract was evaluated via flow cytometric immunophenotyping. However, no specific compound with corresponding efficacy could be identified.
In the second, main project of this dissertation, the safety of herbal products was evaluated in the context of the treatment of nonpsychotic mental disorders in pregnancy. The herbal preparations included in this project were St. John´s wort (Hypericum perforatum), California poppy (Eschscholzia californica), Valerian (Valeriana officinalis), Lavender (Lavandula angustifolia) and Hops (Humulus lupulus). All of these are commonly used in the treatment of nonpsychotic mental disorders; however, due to their traditional use, they have been only poorly characterised for their safety. In a major effort, a multi-centre, multidisciplinary project aimed at providing the crucially required data on the safety of these preparations was undertaken.
As part of this effort, the toxic and modulatory properties of the extracts and the corresponding constituents were assessed in a variety of assays (cytotoxicity, genotoxicity, and functional) in a placental cell line and primary human immune cells. These two model systems were chosen for their crucial functions in all stages of pregnancy.
None of the extracts exhibited genotoxic, cytotoxic or functional effects, at physiologically relevant concentrations in both models. Only in the artificially high concentration of 100 µg/mL statistically significant cytotoxicity was identified for the extracts from St. Johnʼs wort, California poppy (very weak effect), valerian, and hops in placental cells. At concentrations of ≥ 30µg/mL the extracts of St. John´s wort and Valerian also induced significant inhibition of lymphocyte proliferation.
Additional testing of the corresponding compounds supported these findings. Protopine (California poppy), valerenic acid (valerian), and linalool (lavender) were essentially ineffective in all placental and immunological assays. Meanwhile, hyperforin and hypericin (St. John´s wort), and valtrate (valerian) induced cytotoxicity, in placental cells, in concentrations higher than 1 µM. In the ex vivo lymphocyte model, these three constituents affected viability and proliferation in concentrations ≥ 3 µM. Immunophenotyping of cells treated with these three compounds exhibited varying results on cytokine production and surface marker expression. Overall, the two St. John´s wort compounds showed a more inhibitory phenotype compared to valtrate which induced stimulation on all the cytokines.
Genotoxicity was reported to be of no concern for all tested substances in both model systems.
Advisors:Gründemann, Carsten and Potterat, Olivier and Heilmann, Jörg
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Translational Complementary Medicine (Gründemann)
UniBasel Contributors:Gründemann, Carsten and Potterat, Olivier
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14952
Thesis status:Complete
Number of Pages:149
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss149528
edoc DOI:
Last Modified:10 Mar 2023 05:30
Deposited On:09 Mar 2023 08:27

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