6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells

Background/Aims: Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs). Methods: We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6-PN and 8-PN on human metastatic melanoma cells. Results: In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 µmol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8-PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis-independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells. Conclusion: The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities

Extraction of prenylflavonoids of Humulus lupulus L. and their effect on differentiation and protection of neural cell cultures

Die Prenylflavonoide des Hopfens weisen ein breites biologisches Wirkungsspektrum auf. Für den Einsatz von Hopfenpräparaten, z.B. in der Phytotherapie sind Kenntnisse über zusätzliche biologische Aktivitäten dieser wenig konzentrierten Inhaltsstoffe außerordentlich wichtig. Durch eine aktivitätsgeführte Fraktionierung gelang in dieser Arbeit die Bestimmung eines niedrig konzentrierten Prenylflavonoids des Hopfens, welches eine stärkere neurogeneseinduzierende Aktivität aufweist als der bekannte Differenzierungsfaktor Retinolsäure. Das für diese Aktivität relevante Strukturmerkmal konnte durch eine Struktur-Wirkungs-Analyse bestimmt werden. Des Weiteren wurde eine einfache und günstige Anreicherungsmethode zur Gewinnung dieser neurogeneseinduzierenden Substanzen entwickelt.Prenylflavonoids of hop show a broad spectrum of biological activities. Knowledge of additional biological activities of minor concentrated ingredients is extremly important for the use of hop phytopharmaceuticals. By an activity guided fractionation a low concentrated prenylflavonoid of hops was determined as neurogenesis inducing factor. This flavonoid shows a higher neurogenesis inducing activity as retinoic acid, a well known factor of differentiation. Additionally the structure characteristic which accounts for this neurogensis inducing activity was identified. Furthermore a cheap and simple method to enrich these neurogenesis inducing compounds was developed

Biocompatible, sustainable coatings based on photo-crosslinkable cellulose derivatives

Materials derived from renewable resources have great potential to replace fossil-based plastics in biomedical applications. In this study, the synthesis of cellulose-based photoresists by esterification with methacrylic acid anhydride and sorbic acid was investigated. These resists polymerize under UV irradiation in the range λ=254 nm to 365 nm, with or even without the use of an additional photoinitiator concerning the sorbic acid derivative. Usability for biomedical applications was demonstrated by investigating the adhesion and viability of a fibrosarcoma cell line (HT-1080). Compared to polystyrene, the material widely used for cell culture dishes, cell adhesion to the biomaterials tested was even stronger, as assessed by a centrifugation assay. This is all the more remarkable since chemical surface modification of cellulose with methacrylate and sorbic acid allows direct attachment of HT-1080 cells without the addition of protein modifiers or ligands. Furthermore, cells on both biomaterials show similar cell viability, not significantly different from polystyrene, indicating no significant impairment or enhancement. This will allow the future use of these cellulose derivatives as support structures for scaffolds or as self-supporting coatings also for cell culture, based solely on renewable and sustainable resources

Historical herbal texts from Switzerland : a potential source for plant- derived natural products against SARS-CoV-2

In search for more effective prophylactic and curative therapeutics against SARS-CoV-2, an ethnopharmcological approach was used to select 20 plants described in the “Arzneibuch von Hallwyl” (ABvH), an influential recipe text from 16th century Switzerland. Plants were selected based on specific historical uses possibly linked with the treatment of microbial or viral infections as well as inflammatory conditions. For each plant candidate, aqueous and hydroethanolic extracts have been produced, respectively. The prophylactic activity of extracts against SARS-CoV-2 was assessed using the CellTiter-Glo​ Luminescent Cell Viability Assay upon viral infection in vitro. Four plants showed promising activity; among them Sambucus nigra L. (leaves) and Artemisia vulgaris L. (aerial parts) showed an anti-SARS-CoV-2 potential both with an activity of≤33.3 µg/mL for their hydroethanolic extract. The findings confirm the historical traditional use in the area of infectious diseases. Accordingly, this study shows supportive evidence that an ethnopharmacological approach combined with robust in vitro methods effectively enables to screen for promising antiviral plant extracts against SARS-CoV-2

Dihydroxyquingdainone Induces Apoptosis in Leukaemia and Lymphoma Cells via the Mitochondrial Pathway in a Bcl-2- and Caspase-3-Dependent Manner and Overcomes Resistance to Cytostatic Drugs In Vitro

Isatis tinctoria and its indigo dyes have already provided highly active anti-leukaemic lead compounds, with the focus mainly being on indirubin, whereas indigo itself is inactive. There are many more indigoids to find in this plant extract, for example, quingdainone, an indigoid derived from tryptanthrin. We present here a new synthesis of hitherto neglected substituted quingdainones, which is very necessary due to their poor solubility behaviour, and a structure-dependent anti-leukaemic activity study of a number of compounds. Substituted α-phenylaminoacrylic acid was synthesised by hydrogen sulfide extrusion from an analogue mercaptoacetic acid, available from the condensation of rhodanin and a substituted tryptanthrin. It is shown that just improving water solubility does not increase anti-leukaemic activity, since a quingdainone carboxylic acid is inactive compared to dihydroxyquingdainone. The most effective compound, dihydroxyquingdainone with an AC50 of 7.5 µmole, is further characterised, revealing its ability to overcome multidrug resistance in leukaemia cells (Nalm-6/BeKa) with p-glycoprotein expression