Publications by authors named "Liselotte Krenn"

65 Publications

Regular consumption of "Nkui", a Cameroonian traditional dish, may protect against cardiovascular and bone disorders in an estrogen deficiency condition.

J Complement Integr Med 2021 Apr 5. Epub 2021 Apr 5.

Department of Chemical Sciences, Faculty of Science, University of Johannesburg, Johannesburg, South Africa.

Objectives: There is a growing body of evidence indicating the potential of culinary herbs and spices to decrease the incidence of several chronic diseases or conditions. Because of this, the WHO recommends their regular consumption. In the Cameroonian culinary practices, "Nkui" is a famous dish made from a mixture of 10 spices. In our previous study, the ethanolic extract of this mixture exhibited promising estrogenic properties. Thus, this study aimed to evaluate its protective effects on some menopause-related cardiovascular and bone disorders.

Methods: For this purpose, a post-menopause-like model (ovariectomized rats) has been used. Animals were orally treated with the "Nkui" extract for 60 days. The investigation focused on the oxidative stress status, endothelial function (NO bioavailability), lipid profile, and bone mass, biochemical (calcium and inorganic phosphorus contents, serum alkaline phosphatase activity) and histomorphological features.

Results: The extract regulated lipid metabolism in a way to prevent accumulation of abdominal fat, gain in body weight and increased atherogenic indexes induced by ovariectomy. It prevented menopause-related low levels of nitric oxide and oxidative stress damage by increasing superoxide dismutase and catalase activities, while reducing glutathione and malondialdehyde levels in the heart and aorta. Moreover, it prevented ovariectomy-induced bone mass loss, bone marrow disparities and the disorganization of the trabecular network. It also increased femur calcium and inorganic phosphorus contents.

Conclusions: These results suggest that a regular consumption of "Nkui" may have health benefits on cardiovascular system and osteoporosis, major health issues associated with menopause.
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http://dx.doi.org/10.1515/jcim-2020-0127DOI Listing
April 2021

Editorial.

Planta Med 2020 10 13;86(15):1048-1049. Epub 2020 Oct 13.

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http://dx.doi.org/10.1055/a-1214-1496DOI Listing
October 2020

Methylated Xanthones from the Rootlets of Display Cytotoxic Activity in Colorectal Cancer Cells.

Molecules 2020 Sep 28;25(19). Epub 2020 Sep 28.

Department of Pharmacognosy, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.

The tree fern (Kunth) C. Presl is common in the rainforests of Central and South America, where suspensions of the dried rhizome are traditionally used to treat intestinal diseases. Two compounds from this plant, 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB), have been shown to be biologically highly active against colorectal cancer (CRC) cells in previous studies. The current investigation resulted in the isolation of the previously undescribed methylated xanthones 2-deprenyl-6--methyl-7-hydroxy-rheediaxanthone B, 2-deprenyl-5--methyl-7-methoxy-rheediaxanthone B, 2-deprenyl-5--methyl- 7-hydroxy-rheediaxanthone B and 2-deprenyl-7-methoxy-rheediaxanthone B. All compounds were isolated by column chromatography, structures were elucidated by one- and two-dimensional NMR-experiments and the identities of the compounds were confirmed by LC-HRMS. In logarithmically growing SW480 CRC cell cultures, cytotoxicity by neutral red uptake and MTT assays as well as caspase activation was analyzed. Cellular targets were examined by Western blot, and topoisomerase I (topo I) inhibition potential was tested. Comparing the structure-activity relationship with XB and OH-XB, the monomethylated derivatives showed qualitatively similar effects/mechanisms to their nonmethylated analogues, while dimethylation almost abolished the activity. Inhibition of topo I was dependent on the presence of an unmethylated 7-OH group.
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http://dx.doi.org/10.3390/molecules25194449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582535PMC
September 2020

Prolongation of metallothionein induction combats Aß and α-synuclein toxicity in aged transgenic Caenorhabditis elegans.

Sci Rep 2020 07 16;10(1):11707. Epub 2020 Jul 16.

Oxford Antibiotic Group GmbH, Konrad-Lorenz-Straße 24, 3430, Tulln, Austria.

Neurodegenerative disorders (ND) like Alzheimer's (AD), Parkinson's (PD), Huntington's or Prion diseases share similar pathological features. They are all age dependent and are often associated with disruptions in analogous metabolic processes such as protein aggregation and oxidative stress, both of which involve metal ions like copper, manganese and iron. Bush and Tanzi proposed 2008 in the 'metal hypothesis of Alzheimer's disease' that a breakdown in metal homeostasis is the main cause of NDs, and drugs restoring metal homeostasis are promising novel therapeutic strategies. We report here that metallothionein (MT), an endogenous metal detoxifying protein, is increased in young amyloid ß (Aß) expressing Caenorhabditis elegans, whereas it is not in wild type strains. Further MT induction collapsed in 8 days old transgenic worms, indicating the age dependency of disease outbreak, and sharing intriguing parallels to diminished MT levels in human brains of AD. A medium throughput screening assay method was established to search for compounds increasing the MT level. Compounds known to induce MT release like progesterone, ZnSO, quercetin, dexamethasone and apomorphine were active in models of AD and PD. Thioflavin T, clioquinol and emodin are promising leads in AD and PD research, whose mode of action has not been fully established yet. In this study, we could show that the reduction of Aß and α-synuclein toxicity in transgenic C. elegans models correlated with the prolongation of MT induction time and that knockdown of MT with RNA interference resulted in a loss of bioactivity.
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http://dx.doi.org/10.1038/s41598-020-68561-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366685PMC
July 2020

Flavonoids Distinctly Stabilize Lymph Endothelial- or Blood Endothelial Disintegration Induced by Colon Cancer Spheroids SW620.

Molecules 2020 Apr 29;25(9). Epub 2020 Apr 29.

Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, A-1090 Vienna, Austria.

The health effects of plant phenolics in vegetables and other food and the increasing evidence of the preventive potential of flavonoids in "Western Diseases" such as cancer, neurodegenerative diseases and others, have gained enormous interest. This prompted us to investigate the effects of 20 different flavonoids of the groups of flavones, flavonols and flavanones in 3D in vitro systems to determine their ability to inhibit the formation of circular chemorepellent induced defects (CCIDs) in monolayers of lymph- or blood-endothelial cells (LECs, BECs; respectively) by 12(S)-HETE, which is secreted by SW620 colon cancer spheroids. Several compounds reduced the spheroid-induced defects of the endothelial barriers. In the SW620/LEC model, apigenin and luteolin were most active and acacetin, nepetin, wogonin, pinocembrin, chrysin and hispidulin showed weak effects. In the SW620/BEC model acacetin, apigenin, luteolin, wogonin, hispidulin and chrysin exhibited weak activity.
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http://dx.doi.org/10.3390/molecules25092066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248751PMC
April 2020

Destabilization of FoxM1 and Inhibition of Topoisomerase I Contribute to Cytotoxicity of Prenylated Xanthones Isolated from Metaxya rostrata.

Planta Med 2020 Oct 5;86(15):1073-1079. Epub 2020 Feb 5.

Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.

We recently isolated the prenylated xanthones 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB) from the South American tree fern . This study explores the mechanisms underlying the FoxM1 downregulation induced by both xanthones. Analysis of cell viability and cell-death induction in SW480, HCT116, Caco-2, DLD1 and HT29 exposed to xanthones found cell-loss and activation of caspase in all cell lines except HT29 that do not have high FoxM1 protein levels. To determine the cellular mechanism of xanthone-induced FoxM1 loss, protein stability was analyzed by cycloheximide-chase experiments and showed reduction of FoxM1 stability by XB but not OH-XB. Destabilization was prevented by inhibiting proteasome activity using MG-132 and moderately by the lysosomal inhibitor bafilomycin A1 (baf A1). OH-XB had a stronger impact than XB on FoxM1 mRNA expression by qRT-PCR, and MG-132 positively affected FoxM1 protein level in OH-XB exposed cells even though no decrease in protein abundance had been induced by the xanthone. Additionally, the compound inhibited topoisomerase I causing DNA DSB and early cell cycle arrest. This may reduce FoxM1 gene expression, which may in turn compromise DNA repair and enhance xanthone-induced cell death. With regard to xanthone-induced cell death, MG-132 protected cultures from cell loss induced by both compounds, and baf A1 was active against these XB-induced effects. In summary, both destabilization of FoxM1 protein and topoisomerase I inhibition contribute to both XB and OH-XB cytotoxic activity albeit at different ratios.
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http://dx.doi.org/10.1055/a-1097-8722DOI Listing
October 2020

A Pharmacological Overview of Alpinumisoflavone, a Natural Prenylated Isoflavonoid.

Front Pharmacol 2019 10;10:952. Epub 2019 Sep 10.

Laboratory of Animal Physiology, Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon.

Over the last decade, several studies demonstrated that prenylation of flavonoids enhances various biological activities as compared to the respective nonprenylated compounds. In line with this, the natural prenylated isoflavonoid alpinumisoflavone (AIF) has been explored for a number of biological and pharmacological effects (therapeutic potential). In this review, we summarize the current information on health-promoting properties of AIF. Reported data evidenced that AIF has a multitherapeutic potential with antiosteoporotic, antioxidant and anti-inflammatory, antimicrobial, anticancer, estrogenic and antiestrogenic, antidiabetic, and neuroprotective properties. However, research on these aspects of AIF is not sufficient and needs to be reevaluated using more appropriate methods and methodology. Further series of studies are needed to confirm these pharmacological effects, and this review should lay the basis for the design of respective investigations. Overall, despite the drawbacks of studies recorded, AIF exhibits a potential as drug candidate.
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http://dx.doi.org/10.3389/fphar.2019.00952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746831PMC
September 2019

Antiplasmodial activity of triterpenes isolated from the methanolic leaf extract of Combretum racemosum P. Beauv.

J Ethnopharmacol 2020 Jan 28;247:112203. Epub 2019 Aug 28.

Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria. Electronic address:

Ethnopharmacological Relevance: Combretum racemosum showed activity in previous ethnopharmacological investigations of some Combretum species used in malaria treatment in parts of West Africa.

Aim Of The Study: This study aimed at confirming the antimalarial potential of this plant by an activity-guided isolation of its active principles.

Materials And Methods: A crude methanolic leaf extract of Combretum racemosum and fractions thereof obtained by partition with chloroform and n-butanol were investigated for antiplasmodial activity against chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains of Plasmodium falciparum. Repeated chromatographic separations were conducted on the chloroform fraction to isolate bioactive compounds for further tests on antiplasmodial activity. The characterization of the isolated substances was performed by applying NMR- and MS-techniques (ESI-MS, HR-ESIMS, 1D and 2D NMR).

Results: The chloroform fraction (D10: IC = 33.8 ± 1.5 μg/mL and W2: IC = 27.8 ± 2.9 μg/mL) exhibited better antiplasmodial activity than the n-butanol fraction (D10: IC = 78.1 ± 7.3 μg/mL and W2: IC = 78 ± 15 μg/mL) as well as the methanolic raw extract (D10: IC = 64.2 ± 2.7 μg/mL and W2: IC = 65.8 ± 14.9 μg/mL). Thus, the focus of the phytochemical investigation was laid on the chloroform fraction, which led to the identification of four ursane-type (19α-hydroxyasiatic acid (1), 6β,23-dihydroxytormentic acid (4), madecassic acid (8), nigaichigoside F1 (10)) and four oleanane-type (arjungenin (2), combregenin (5), terminolic acid (7), arjunglucoside I (11)) triterpenes, as well as abscisic acid (9). Compounds 1 and 2, 4 and 5, 7 and 8 as well as 10 and 11 were isolated as isomeric mixtures in fractions CR-A, CR-C, CR-E and CR-H, respectively. All isolated compounds and mixtures exhibited moderate to low activity, with madecassic acid being most active (D10: IC = 28 ± 12 μg/mL and W2: IC = 17.2 ± 4.3 μg/mL).

Conclusion: This paper reports for the first time antiplasmodial principles from C. racemosum and thereby gives reason to the traditional use of the plant.
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http://dx.doi.org/10.1016/j.jep.2019.112203DOI Listing
January 2020

Dandelion is more tolerant to cadmium than to nickel excess.

Chemosphere 2019 Jun 27;224:884-891. Epub 2019 Feb 27.

Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090, Vienna, Austria.

Comparative accumulation of cadmium (Cd) and nickel (Ni) and the consequences for the metabolism of common weed dandelion (triploid ones of Taraxacum sect. Taraxacum) were studied here for the first time. Cd accumulated more in both shoots and roots (489 and 2486 μg/g DW) than Ni (165 and 858 μg/g DW) after 14 days of exposure and only root Ni content did not increase between 7 and 14 days of exposure. Surprisingly, though Ni was less accumulated than Cd, it had more negative impact on basic physiology (root dry biomass, shoot water content and chlorophyll amount). Ni also evoked more extensive depression of mineral nutrients (K, Ca, Mg, and Mn) in the shoots than Cd while root potassium content was elevated by both metals. Ni suppressed accumulation of total thiols but anatomical changes and ROS formation (detected by fluorescence microscopy of total ROS and lipid peroxidation) were induced more by Cd. Total soluble phenols, major (caftaric and cichoric) and minor (chlorogenic and caffeic) phenolic acids were elevated by both metals and rather increased with prolonged exposure in the shoots (14 versus 7 days). On the contrary, typically depletion of these metabolites was found in the roots after prolonged exposure to Ni, but not to Cd. Data showed distinct toxicity of Cd and Ni in dandelion. More expressive tolerance of dandelion to Cd than to Ni indicates its potential use for the remediation of Cd-contaminated environment.
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http://dx.doi.org/10.1016/j.chemosphere.2019.02.181DOI Listing
June 2019

Prenylated xanthones from Metaxya rostrata suppress FoxM1 and induce active cell death by distinct mechanisms.

Phytomedicine 2019 Jul 2;60:152912. Epub 2019 Apr 2.

Medical University Vienna, Department of Medicine I, Institute of Cancer Research, Borschkegasse 8a, 1090 Vienna, Austria. Electronic address:

Background: Metaxya rostrata C.Presl (Metaxyaceae) is a tree fern widespread in Central and South America and the dried rhizome is used in ethnic medicine against intestinal ulcers or tumors. An activity-guided isolation resulted in two structurally related xanthones: 2-deprenyl-rheediaxanthone B (XB) and 2-deprenyl-7-hydroxy-rheediaxanthone B (OH-XB).

Hypothesis/purpose: This study analyzed the cytotoxic activity and underlying cellular mechanisms of OH-XB for the first time in comparison to XB.

Methods: We exposed the colorectal cancer cell line SW480 and F331 fibroblasts to XB and OH-XB and determined cell viability by neutral red uptake and nuclear morphology by staining with Hoechst dye. Cell cycle distribution and the mechanism of cell death were analyzed by FACS and western blot. Knockdown of FoxM1 expression was performed with siRNA.

Results: OH-XB was at least as cytotoxic as XB in the induction of cell cycle arrest and active cell death. While both compounds strongly inhibited the transcription factor FoxM1, the cellular mechanisms of growth arrest and cell death induction differed widely: OH-XB induced S-phase cell cycle arrest in contrast to a G2-M-phase arrest by XB. It caused morphological modifications typical for classical apoptosis with increased caspase 7 activity and enhanced cleavage of PARP, while XB caused caspase 2 activation and mitotic catastrophe. After knockdown of FoxM1 expression no induction of caspase activity could be observed.

Conclusion: In summary, our data clearly showed that XB and OH-XB are promising new lead compounds for cancer therapy with distinct cellular mechanisms. Both compounds are candidates for further pre-clinical and clinical investigations.
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http://dx.doi.org/10.1016/j.phymed.2019.152912DOI Listing
July 2019

Chemical Composition of and the Effects on Tumor Invasiveness .

Front Pharmacol 2018 3;9:304. Epub 2018 Apr 3.

Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria.

A detannified methanolic extract of L. attenuated the formation of cancer cell-induced circular chemorepellent induced defects (CCIDs) in the lymph endothelial cell barrier, which resemble entry ports for the intravasating tumor into the vasculature as a prerequisite for lymph node metastasis. Therefore, the composition of this extract was studied in an activity-guided approach. Since no data on the secondary metabolites of this plant were available, first phytochemical data were collected in the course of the fractionation of the extract. The study resulted in the identification of 14 substances, among them very rare iridoids, such as scrovalentinoside or koelzioside, and several flavonoids (e.g., nepitrin and homoplantaginin). One of the latter group, 2″--acetyl-homoplantaginin, is a new natural compound. In the most active fraction, the flavonoid hispidulin was identified as major component and the assay of the pure compound confirmed a contribution of hispidulin to the CCID-inhibitory effects of . The activity of the two major iridoids in this assay was less compared to hispidulin.
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http://dx.doi.org/10.3389/fphar.2018.00304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891616PMC
April 2018

Apigenin and Luteolin Attenuate the Breaching of MDA-MB231 Breast Cancer Spheroids Through the Lymph Endothelial Barrier .

Front Pharmacol 2018 14;9:220. Epub 2018 Mar 14.

Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.

Flavonoids, present in fruits, vegetables and traditional medicinal plants, show anticancer effects in experimental systems and are reportedly non-toxic. This is a favorable property for long term strategies for the attenuation of lymph node metastasis, which may effectively improve the prognostic states in breast cancer. Hence, we studied two flavonoids, apigenin and luteolin exhibiting strong bio-activity in various test systems in cancer research and are readily available on the market. This study has further advanced the mechanistic understanding of breast cancer intravasation through the lymphatic barrier. Apigenin and luteolin were tested in a three-dimensional (3-D) assay consisting of MDA-MB231 breast cancer spheroids and immortalized lymph endothelial cell (LEC) monolayers. The 3-D model faithfully resembles the intravasation of breast cancer emboli through the lymphatic vasculature. Western blot analysis, intracellular Ca determination, EROD assay and siRNA transfection revealed insights into mechanisms of intravasation as well as the anti-intravasative outcome of flavonoid action. Both flavonoids suppressed pro-intravasative trigger factors in MDA-MB231 breast cancer cells, specifically MMP1 expression and CYP1A1 activity. A pro-intravasative contribution of FAK expression in LECs was established as FAK supported the retraction of the LEC monolayer upon contact with cancer cells thereby enabling them to cross the endothelial barrier. As mechanistic basis, MMP1 caused the phosphorylation (activation) of FAK at Tyr397 in LECs. Apigenin and luteolin prevented MMP1-induced FAK activation, but not constitutive FAK phosphorylation. Luteolin, unlike apigenin, inhibited MMP1-induced Ca release. Free intracellular Ca is a central signal amplifier triggering LEC retraction through activation of the mobility protein MLC2, thereby enhancing intravasation. FAK activity and Ca levels did not correlate. This implicates that the pro-intravasative contribution of FAK and of Ca release in LECs was independent of each other and explains the better anti-intravasative effects of luteolin . In specific formulations, flavonoid concentrations causing significant anti-intravasative effects, can certainly be achieved . As the therapeutic strategy has to be based on permanent flavonoid treatment both the beneficial and adverse effects have to be investigated in future studies.
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http://dx.doi.org/10.3389/fphar.2018.00220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861143PMC
March 2018

Natural Terpenoids Against Female Breast Cancer: A 5-year Recent Research.

Curr Med Chem 2018 ;25(27):3162-3213

Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.

Background: The approval of Taxol® in 1993 marked the great entrance of terpenoids in the anti-cancer area and this drug is still highly important in the treatment of refractory ovarian, breast and other cancers. Over decades, other prominent natural terpenoids have become indispensable for the modern pharmacotherapy of breast cancer. However, given the rapid evolution of drug resistance, effective treatments for advanced breast cancers requiring cytotoxic chemotherapy represent a major unmet clinical need. Therefore, innovative agents effective in long-term chemotherapy are urgently needed.

Objective: This review examines recent advances/research about natural terpenoids, and their mechanisms against female breast cancer over the period covering January 1st, 2012 to December 31st, 2016.

Results: Carcinogenesis constitutes a multistep process wherein each stage is characterized by distinct phenotypic changes. Numerous chemicals recorded in this review have been shown to significantly inhibit proliferation, migration, apoptosis resistance, tumor angiogenesis or metastasis in different breast cancer cells/tumours in vitro and in vivo. Targeting simultaneously several or all these aspects/steps of cancer progression could be an advantage. In line with this, phytochemicals such as thymoquinone (8), costunolide (46), tanshinone IIA (132), triptolide (136), cucurbitacin B (179), celastrol (226) and lycopene (238) had caught our attention.

Conclusion: These compounds appear to be promising to overcome breast cancer treatment failure. However, despite the interesting activities, additional preclinical investigations are needed in further breast cancer cell/tumor models in vitro and in vivo.
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http://dx.doi.org/10.2174/0929867325666180214110932DOI Listing
September 2018

Intravasation of SW620 colon cancer cell spheroids through the blood endothelial barrier is inhibited by clinical drugs and flavonoids in vitro.

Food Chem Toxicol 2018 Jan 10;111:114-124. Epub 2017 Nov 10.

Clinical Institute of Pathology, Medical University of Vienna, Austria. Electronic address:

Mechanisms how colorectal cancer (CRC) cells penetrate blood micro-vessel endothelia and metastasise is poorly understood. To study blood endothelial cell (BEC) barrier breaching by CRC emboli, an in vitro assay measuring BEC-free areas underneath SW620 cell spheroids, so called "circular chemorepellent induced defects" (CCIDs, appearing in consequence of endothelial retraction), was adapted and supported by Western blotting, EIA-, EROD- and luciferase reporter assays. Inhibition of ALOX12 or NF-κB in SW620 cells or BECs, respectively, caused attenuation of CCIDs. The FDA approved drugs vinpocetine [inhibiting ALOX12-dependent 12(S)-HETE synthesis], ketotifen [inhibiting NF-κB], carbamazepine and fenofibrate [inhibiting 12(S)-HETE and NF-κB] significantly attenuated CCID formation at low μM concentrations. In the 5-FU-resistant SW620-R/BEC model guanfacine, nifedipine and proadifen inhibited CCIDs stronger than in the naïve SW620/BEC model. This indicated that in SW620-R cells formerly silent (yet unidentified) genes became expressed and targetable by these drugs in course of resistance acquisition. Fenofibrate, and the flavonoids hispidulin and apigenin, which are present in medicinal plants, spices, herbs and fruits, attenuated CCID formation in both, naïve- and resistant models. As FDA-approved drugs and food-flavonoids inhibited established and acquired intravasative pathways and attenuated BEC barrier-breaching in vitro, this warrants testing of these compounds in CRC models in vivo.
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http://dx.doi.org/10.1016/j.fct.2017.11.015DOI Listing
January 2018

In memoriam Prof. Dr. med. Dr. h.c. mult. Fritz H. Kemper (1927-2017).

Phytomedicine 2017 09 12;33:77. Epub 2017 Jun 12.

On behalf of ESCOP, Notaries House, Chapel Street, Exeter, Devon, EX1 1EZ, United Kingdom.

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http://dx.doi.org/10.1016/j.phymed.2017.06.003DOI Listing
September 2017

Acetylated Furostene Glycosides from Solanum gilo Fruits.

Planta Med 2017 Oct 18;83(14-15):1227-1232. Epub 2017 Jul 18.

Department of Pharmacognosy, University of Vienna, Vienna, Austria.

In continuation of our work on a traditional mixture of spices called "Nkui", used in Cameroon for its influence on women's reproductive health, we investigated the chemical composition of , one component of "Nkui". A methanolic extract was studied in detail. After dereplication of several known compounds, two furo-5-stene-derived saponin glycosides with acetylated sugar moieties were isolated. By extensive 1- and 2D NMR experiments and HR-MS and GC-MS methods, the structures were elucidated as 26-[(3‴,4‴,6‴-tri-O-acetyl)--D-glucopyranosyloxy]-22-hydroxyfurost-5-en-3-yl-O--L-rhamnopyranosyl-(1″→2')--D-glucopyranoside () and 26-[(3‴,4‴,6‴-tri-O-acetyl)--D-glucopyranosyloxy]-22-hydroxyfurost-5-en-3-yl-[O--L-rhamnopyranosyl-(1''''→4')-O--L-rhamnopyranosyl-(1″→2')]--D-glucopyranoside (), both new natural compounds.
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http://dx.doi.org/10.1055/s-0043-116491DOI Listing
October 2017

Erythrodiol, an Olive Oil Constituent, Increases the Half-Life of ABCA1 and Enhances Cholesterol Efflux from THP-1-Derived Macrophages.

Front Pharmacol 2017 13;8:375. Epub 2017 Jun 13.

Department of Pharmacognosy, University of ViennaVienna, Austria.

Cholesterol efflux (ChE) from macrophages is an initial step of reverse cholesterol transport (RCT). The ATP-binding cassette transporter A1 (ABCA1) is a key transporter for ChE and its increased expression is regarded to attenuate atherosclerosis. Thus, the identification and characterization of molecules raising ABCA1 and thereby stimulating ChE is of pharmacological relevance. In this study, we tested dietary compounds from olive oil for their capacity of enhancing cellular ABCA1 protein level. We identified erythrodiol (Olean-12-ene-3β,28-diol) as an ABCA1 stabilizer and revealed its positive influence on ChE in THP-1-derived human macrophages. Among the nine tested compounds from olive oil, erythrodiol was the sole compound raising ABCA1 protein level (at 10 μM). None of the tested compounds impaired viability of THP-1 macrophages from 5 to 20 μM as determined by resazurin conversion. Western blot analyses of key membrane transporters contributing to ChE showed that the protein level of ABCG1 and scavenger receptor class B member 1 (SR-B1) remain unaffected by erythrodiol. Besides, erythrodiol (10 μM) did not influence the mRNA level of ABCA1, ABCG1, and SR-B1, as determined by quantitative reverse transcription PCR, but significantly inhibited the degradation of ABCA1 as evident by an increased half-life of the protein in the presence of cycloheximide, an inhibitor of protein synthesis. Therefore, erythrodiol promotes ChE from THP-1-derived human macrophages by stabilizing the ABCA1 protein. This bioactivity makes erythrodiol a good candidate to be further explored for therapeutic or preventive application in the context of atherosclerosis.
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http://dx.doi.org/10.3389/fphar.2017.00375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5468437PMC
June 2017

The ESCOP-monographs for universities.

Phytomedicine 2017 07 15;31:10. Epub 2017 May 15.

ESCOP, Notaries House, Chapel Street, Exeter, Devon, EX1 1EZ, United Kingdom.

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http://dx.doi.org/10.1016/j.phymed.2017.05.004DOI Listing
July 2017

Fenofibrate inhibits tumour intravasation by several independent mechanisms in a 3-dimensional co-culture model.

Int J Oncol 2017 May 7;50(5):1879-1888. Epub 2017 Apr 7.

Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.

Lymph node metastasis of breast cancer is a clinical marker of poor prognosis. Yet, there exist no therapies targeting mechanisms of intravasation into lymphatics. Herein we report on an effect of the antidyslipidemic drug fenofibrate with vasoprotective activity, which attenuates breast cancer intravasation in vitro, and describe the potential mechanisms. To measure intravasation in a 3-dimensional co-culture model MDA-MB231 and MCF-7 breast cancer spheroids were placed on immortalised lymphendothelial cell (LEC) monolayers. This provokes the formation of circular chemorepellent induced defects (CCIDs) in the LEC barrier resembling entry ports for the intravasating tumour. Furthermore, the expression of adhesion molecules ICAM-1, CD31 and FAK was investigated in LECs by western blotting as well as cell-cell adhesion and NF-κB activity by respective assays. In MDA-MB231 cells the activity of CYP1A1 was measured by EROD assay. Fenofibrate inhibited CCID formation in the MDA-MB231/LEC- and MCF-7/LEC models and the activity of NF-κB, which in turn downregulated ICAM-1 in LECs and the adhesion of cancer cells to LECs. Furthermore, CD31 and the activity of FAK were inhibited. In MDA-MB231 cells, fenofibrate attenuated CYP1A1 activity. Combinations with other FDA-approved drugs, which reportedly inhibit different ion channels, attenuated CCID formation additively or synergistically. In summary, fenofibrate inhibited NF-κB and ICAM-1, and inactivated FAK, thereby attenuating tumour intravasation in vitro. A combination with other FDA-approved drugs further improved this effect. Our new concept may lead to a novel therapy for cancer patients.
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http://dx.doi.org/10.3892/ijo.2017.3956DOI Listing
May 2017

Potential Antiosteoporotic Natural Product Lead Compounds That Inhibit 17β-Hydroxysteroid Dehydrogenase Type 2.

J Nat Prod 2017 04 20;80(4):965-974. Epub 2017 Mar 20.

Division of Molecular & Systems Toxicology, University of Basel , Klingelbergstraße 50, 4056 Basel, Switzerland.

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) converts the active steroid hormones estradiol, testosterone, and 5α-dihydrotestosterone into their weakly active forms estrone, Δ-androstene-3,17-dione, and 5α-androstane-3,17-dione, respectively, thereby regulating cell- and tissue-specific steroid action. As reduced levels of active steroids are associated with compromised bone health and onset of osteoporosis, 17β-HSD2 is considered a target for antiosteoporotic treatment. In this study, a pharmacophore model based on 17β-HSD2 inhibitors was applied to a virtual screening of various databases containing natural products in order to discover new lead structures from nature. In total, 36 hit molecules were selected for biological evaluation. Of these compounds, 12 inhibited 17β-HSD2 with nanomolar to low micromolar IC values. The most potent compounds, nordihydroguaiaretic acid (1), IC 0.38 ± 0.04 μM, (-)-dihydroguaiaretic acid (4), IC 0.94 ± 0.02 μM, isoliquiritigenin (6), IC 0.36 ± 0.08 μM, and ethyl vanillate (12), IC 1.28 ± 0.26 μM, showed 8-fold or higher selectivity over 17β-HSD1. As some of the identified compounds belong to the same structural class, structure-activity relationships were derived for these molecules. Thus, this study describes new 17β-HSD2 inhibitors from nature and provides insights into the binding pocket of 17β-HSD2, offering a promising starting point for further research in this area.
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http://dx.doi.org/10.1021/acs.jnatprod.6b00950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411959PMC
April 2017

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca signalling.

Cell Mol Life Sci 2017 05 24;74(10):1907-1921. Epub 2016 Dec 24.

Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca levels were measured and pharmacological- or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca, Ca-calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca release. Thus, Ca signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour-stroma interaction.
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http://dx.doi.org/10.1007/s00018-016-2441-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390003PMC
May 2017

Rare phenolic structures found in the aerial parts of Eriosema laurentii De Wild.

Phytochemistry 2016 Aug 7;128:5-11. Epub 2016 May 7.

Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. Electronic address:

Recent pharmacological and toxicological investigations of Eriosema laurentii (Leguminosae) have underlined the plausibility of the use of this plant in traditional African medicine. A very complex pattern of phenolic compounds was detected in the tested extracts. Based on these preceding results a detailed phytochemical study was performed and resulted in the isolation and identification of eleven compounds. All are reported in this plant for the first time and four of those are previously undescribed secondary metabolites: 3,4',6,8-tetrahydroxyflavanone-7-C-glucoside and 3,4',6,8-tetrahydroxyflavone-7-C-glucoside with an extremely rare substitution pattern as well as 1-[2,4-dihydroxy-3-(2-hydroxy-3-methylbut-3-en-1-yl)phenyl]-3-phenylpropan-1-one and 1-[2,4-dihydroxy-3-(2-hydroxy-3-methylbut-3-en-1-yl)phenyl]-3-(4-methoxyphenyl)-propan-1-one. Their structures were elucidated unambiguously by extensive MS- and NMR-experiments.
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http://dx.doi.org/10.1016/j.phytochem.2016.03.020DOI Listing
August 2016

Estrogenic properties of spices of the traditional Cameroonian dish "Nkui" in ovariectomized Wistar rats.

J Complement Integr Med 2016 Jun;13(2):151-62

Background: Besides the basic role to flavor and color foods, several health benefits have been attributed to spices. The traditional Cameroonian food "Nkui" is prepared using several spices (Afrostyrax lepidophyllus Mildbr., Capsicum frutescens Linn., Fagara leprieurii Guill. et Perr., Fagara tessmannii Engl., Mondia whitei Hook. F. Skell., Pentadiplandra brazzeana Baill., Solanum gilo Raddi., Tetrapleura tetraptera Taub. and Xylopia parviflora A. Rich. Benthane) that are believed to have a positive impact on the female reproductive physiology. Aiming to determine the potential effect of this food on the female reproductive tract, we evaluated the estrogenic properties of aqueous and ethanol extracts of Nkui using a 3-day uterotrophic assay in ovariectomized (OVX) rats.

Methods: OVX female Wistar rats were randomly separated in several groups of five animals each and submitted to a 3-day uterotrophic assay (per os). At the end of treatment, animals were sacrificed and uterus, vagina and mammary gland collected and fixed in 10 % formalin for histological analysis.

Results: These extracts increased the uterine wet weight, the uterine and vaginal epithelial heights, and the lumen and diameter of alveoli in the mammary glands. They also altered the estradiol-induced increase of uterine wet weight. The dichloromethane and methanol fractions of the ethanol extract exhibited estrogenic properties as well by increasing uterine and vaginal endpoints.

Conclusions: These results suggest that the spices of "Nkui" contain estrogenic phytoconstituents and this traditional food may be considered as functional.
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http://dx.doi.org/10.1515/jcim-2015-0096DOI Listing
June 2016

Trophosome of the Deep-Sea Tubeworm Riftia pachyptila Inhibits Bacterial Growth.

PLoS One 2016 5;11(1):e0146446. Epub 2016 Jan 5.

Department of Limnology and Bio-Oceanography, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.

The giant tubeworm Riftia pachyptila lives in symbiosis with the chemoautotrophic gammaproteobacterium Cand. Endoriftia persephone. Symbionts are released back into the environment upon host death in high-pressure experiments, while microbial fouling is not involved in trophosome degradation. Therefore, we examined the antimicrobial effect of the tubeworm's trophosome and skin. The growth of all four tested Gram-positive, but only of one of the tested Gram-negative bacterial strains was inhibited by freshly fixed and degrading trophosome (incubated up to ten days at either warm or cold temperature), while no effect on Saccharomyces cerevisiae was observed. The skin did not show antimicrobial effects. A liquid chromatography-mass spectrometric analysis of the ethanol supernatant of fixed trophosomes lead to the tentative identification of the phospholipids 1-palmitoleyl-2-lyso-phosphatidylethanolamine, 2-palmitoleyl-1-lyso-phosphatidylethanolamine and the free fatty acids palmitoleic, palmitic and oleic acid, which are known to have an antimicrobial effect. As a result of tissue autolysis, the abundance of the free fatty acids increased with longer incubation time of trophosome samples. This correlated with an increasing growth inhibition of Bacillus subtilis and Listeria welshimeri, but not of the other bacterial strains. Therefore, the free fatty acids produced upon host degradation could be the cause of inhibition of at least these two bacterial strains.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146446PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701499PMC
June 2016

Flavonoids as chemotaxonomic markers in the genus Drosera.

Phytochemistry 2015 Oct 2;118:74-82. Epub 2015 Sep 2.

Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. Electronic address:

The botanical classification of the huge genus Drosera remains controversial since long. In the present study, the pattern of major phenolic compounds in ten Drosera species belonging to seven different subgenera and/or sections of the genus was investigated for chemotaxonomic allocation. The composition of flavonoids and ellagic acid derivatives in Drosera adelae, Drosera burmannii, Drosera dielsiana, Drosera hilaris, Drosera montana, Drosera petiolaris, and Drosera pygmaea was elucidated for the first time. The scarce data on these compounds in Drosera binata, Drosera aliciae, and Drosera spatulata were complemented significantly. Detailed LC-DAD-MS, LC-NMR, and offline 1D and 2D NMR analyses resulted in the unambiguous identification of around 40 different substances, three of them (8-hydroxy-luteolin-8-O-arabinopyranoside, tricetin-7-O-xylopyranoside and 8-hydroxytricetin-8-O-arabinopyranoside) being natural products described for the first time. The distribution of the compounds characterized underlines their potential to serve as chemotaxonomic markers in this genus.
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http://dx.doi.org/10.1016/j.phytochem.2015.08.017DOI Listing
October 2015

A critical overview on Thymus daenensis Celak.: phytochemical and pharmacological investigations.

J Integr Med 2015 Mar;13(2):91-8

Department of Pharmacognosy, University of Vienna, Vienna, Austria.

Thymus daenensis Celak. is an herb endemic to Iran belonging to the Lamiaceae family. Growing in many parts of Iran, the plant is extensively used in folk medicine. This review was performed to compile phytochemical and pharmacological data of T. daenensis. Databases such as PubMed, Scopus, Web of Science, ScienceDirect, Scientific Information Database, Embase, IranMedex and Google Scholar were searched for the terms "Thymus daenensis" and "Avishan-e-denaii" up to 1st January 2014. Following reported ethnopharmacological uses, various T. daenensis preparations have been investigated for antimicrobial, antioxidant, insecticidal and immunomodulatory effects in recent studies. Moreover, numerous studies have been published on the composition of the herb's essential oil, focusing either on environmental parameters or preparation methods. Due to its high concentration of thymol, the plant's essential oil possesses high antimicrobial activities on human pathogenic strains. However, comprehensive studies on the toxicity and teratogenicity as well as clinical efficacy of Thymus daenensis are missing.
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http://dx.doi.org/10.1016/S2095-4964(15)60166-2DOI Listing
March 2015

25 years of ESCOP--a story of success.

Phytomedicine 2014 Oct 21;21(12):A1-2. Epub 2014 Oct 21.

ESCOP, Argyle House, Gandy Street, Exeter, Devon EX4 3LS, United Kingdom.

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http://dx.doi.org/10.1016/j.phymed.2014.08.010DOI Listing
October 2014

Phytochemical and pharmacological aspects of Salvia mirzayanii Rech. f. & Esfand.

J Evid Based Complementary Altern Med 2015 Jan 19;20(1):65-72. Epub 2014 Oct 19.

Department of Pharmacognosy, University of Vienna, Vienna, Austria.

Salvia mirzayanii Rech. f. & Esfand is an endemic herbaceous plant belonging to the Lamiaceae family. The plant grows in the center and south of Iran and is broadly used in folk medicine. This review focuses on phytochemical and pharmacological data of S mirzayanii. Databases such as PubMed, Scopus, Web of Science, Scientific Information Database (Iranian database involving English and Persian articles), and Google Scholar were searched for terms "Salvia mirzayanii," "Iranian sage," "Marv-e-Talkh," and "Moor-e-Talkh" in both Persian and English up to December 10, 2013. In line with the ethnopharmacological uses, antioxidant, immunomodulatory, anti-inflammatory, antimicrobial, and insecticidal activities of different preparations of S mirzayanii have been shown in recent studies. The antimicrobial activity against human pathogenic strains has mainly been attributed to the essential oil of S mirzayanii, which in numerous analyses has been investigated either in plants of different origin or prepared by differing extraction methods. Despite the studies on antioxidant or antimicrobial activities, profound research on the toxicity or clinical properties of the herb is missing.
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http://dx.doi.org/10.1177/2156587214553938DOI Listing
January 2015

Preparative isolation of oleocanthal, tyrosol, and hydroxytyrosol from olive oil by HPCCC.

Food Chem 2015 Mar 23;170:154-9. Epub 2014 Aug 23.

Department of Pharmacognosy, University of Vienna, Vienna, Austria.

For the provision of oleocanthal (OLC), a phenolic compound with very promising pharmacological properties, isolation from olive oil is a very important option. Due to the compound's sensitivity to decomposition upon exposure to oxygen and light, a very gentle isolation method has been developed under use of high performance countercurrent chromatography (HPCCC). By partition of olive oil between hexane and methanol, an extract enriched in phenolics was prepared and subjected to a two-step HPCCC separation under use of heptane-EtOAc-MeOH-H2O mixtures in normal-phase and reverse phase mode, respectively. With this method, the isolation of tyrosol, hydroxytyrosol, and the mixture of (3S,4E)- and (3S,4Z)-OLC was achieved in approx. 70 min for each step. By one- and two-dimensional NMR-experiments and LC-MS, the equilibrium of (3S,4E)- and (3S,4Z)-OLC in such olive oil extracts has unambiguously been proven for the first time.
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http://dx.doi.org/10.1016/j.foodchem.2014.08.079DOI Listing
March 2015

Lupinalbin A as the most potent estrogen receptor α- and aryl hydrocarbon receptor agonist in Eriosema laurentii de Wild. (Leguminosae).

BMC Complement Altern Med 2014 Aug 9;14:294. Epub 2014 Aug 9.

Department of Pharmacognosy, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.

Background: Eriosema laurentii De Wild. (Leguminosae) is a plant used in Cameroon against infertility and gynecological or menopausal complaints. In our previous report, a methanol extract of its aerial parts was shown to exhibit estrogenic and aryl hydrocarbon receptor agonistic activities in vitro and to prevent menopausal symptoms in ovariectomized Wistar rats.

Methods: In order to determine the major estrogen receptor α (ERα) agonists in the extract, an activity-guided fractionation was performed using the ERα yeast screen. To check whether the ERα active fractions/compounds also accounted for the aryl hydrocarbon receptor (AhR) agonistic activity of the crude methanol extract, they were further tested on the AhR yeast screen.

Results: This study led to the identification of 2'-hydroxygenistein, lupinalbin A and genistein as major estrogenic principles of the extract. 2'-hydroxygenistein and lupinalbin A were, for the first time, also shown to possess an AhR agonistic activity, whereas genistein was not active in this assay. In addition, it was possible to deduce structure-activity relationships.

Conclusions: These results suggest that the identified compounds are the major active principles responsible for the estrogenic and AhR agonistic activities of the crude methanol extract of the aerial parts of Eriosema laurentii.
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http://dx.doi.org/10.1186/1472-6882-14-294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138381PMC
August 2014