CC BY-NC-ND 4.0 · Planta Med 2023; 89(15): 1493-1504
DOI: 10.1055/a-2173-8627
Biological and Pharmacological Activity
Original Papers

Exploring Immune Modulatory Effects of Cyclotide-Enriched Viola tricolor Preparations

Bernhard Retzl
1   Center for Physiology and Pharmacology, Medical University of Vienna, Austria
Amy Marisa Zimmermann-Klemd
2   Translational Complementary Medicine, Department of Pharmaceutical Sciences, University of Basel, Switzerland
Moritz Winker
2   Translational Complementary Medicine, Department of Pharmaceutical Sciences, University of Basel, Switzerland
Sven Nicolay
2   Translational Complementary Medicine, Department of Pharmaceutical Sciences, University of Basel, Switzerland
Carsten Gründemann
2   Translational Complementary Medicine, Department of Pharmaceutical Sciences, University of Basel, Switzerland
1   Center for Physiology and Pharmacology, Medical University of Vienna, Austria
› Author Affiliations
This project was supported by the Wilhelm Doerenkamp Foundation through a Natvantage Grant 2019 awarded to C. W. G. and C. G.


Viola tricolor is a medicinal plant with documented application as an anti-inflammatory herb. The standard of care for the treatment of inflammatory bowel disease is immunosuppressive therapeutics or biologics, which often have undesired effects. We explored V. tricolor herbal preparations that are rich in an emerging class of phytochemicals with drug-like properties, so-called cyclotides. As an alternative to existing inflammatory bowel disease medications, cyclotides have immunomodulatory properties, and their intrinsic stability allows for application in the gastrointestinal tract, for instance, via oral administration. We optimized the isolation procedure to improve the yield of cyclotides and compared the cellular effects of violet-derived organic solvent-extracts, aqueous preparations, and an isolated cyclotide from this plant on primary human T lymphocytes and macrophages, i.e., cells that are crucial for the initiation and progression of inflammatory bowel disease. The hot water herbal decoctions have a stronger immunosuppressive activity towards proliferation, interferon-γ, and interleukin-21 secretion of primary human T cells than a DCM/MeOH cyclotide-enriched extract, and the isolated cyclotide kalata S appears as one of the active components responsible for the observed effects. This effect was increased by a longer boiling duration. In contrast, the DCM/MeOH cyclotide-enriched extract was more effective in reducing the levels of cytokines interleukin-6, interleukin-12, interleukin-23, tumor necrosis factor-α, and C – X-C motif chemokine ligand 10, secreted by human monocyte-derived macrophages. Defined cyclotide preparations of V. tricolor have promising pharmacological effects in modulating immune cell responses at the cytokine levels. This is important towards understanding the role of cyclotide-containing herbal drug preparations for future applications in immune disorders, such as inflammatory bowel disease.

Supporting Information

Publication History

Received: 14 April 2023

Accepted after revision: 31 August 2023

Article published online:
25 September 2023

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