Most BRAF-mutant melanoma patients experience a fulminate relapse after several months of treatment with BRAF/MEK inhibitors. To improve therapeutic efficacy, natural plant-derived compounds might be considered as potent additives. Here, we show that magnolol, a constituent of Magnolia officinalis, induced G1 arrest, apoptosis and cell death in BRAF- and NRAS-mutant melanoma cells at low concentration, with no effect in BRAF- and NRAS wild-type melanoma cells and human keratinocytes. This was confirmed in a 3D spheroid model. The apoptosis-inducing effect of magnolol was completely rescued by activating Akt suggesting a mechanism relying primarily on Akt signaling. Magnolol significantly downregulated the PI3K/Akt pathway which led to a global decrease of the active histone mark H3K4me3. Alongside, the repressive histone mark H3K9me3 was increased as a response to DNA damage. Magnolol-induced alterations of histone modifications are reversible upon activation of the Akt pathway. Magnolol-induced a synergistic effect in combination with either BRAF/MEK inhibitors dabrafenib/trametinib or docetaxel at a lower concentration than usually applied in melanoma patients. Combination of magnolol with targeted therapy or chemotherapy also led to analogous effects on histone marks, which was rescued by Akt pathway activation. Our study revealed a novel epigenetic mechanism of magnolol-induced cell death in melanoma. Magnolol might therefore be a clinically useful addition to BRAF/MEK inhibitors with enhanced efficacy delaying or preventing disease recurrence.

Contextual odors can serve as retrieval cues when applied during encoding and recall/recognition of information. To investigate the neuronal basis of these observations, we collected functional MRI data while participants (n=51) performed an encoding and recognition memory task during which odors (congruent: CO or incongruent: IO) were presented as contextual cues. Recognition performance was not influenced by odor, but there was increased activation in the piriform cortex during successful encoding in the CO group, possibly indicating enhanced retrieval of information previously integrated with an olfactory percept. Moreover, group-independent component analysis revealed a stronger task-modulation of subcortical networks for IO versus CO during the recognition task, pointing to differences in olfactory processing. These observations provide a deeper understanding of the involvement of functional neuronal networks in memory tasks and a basis for further evaluation of the impact of odor contexts.

As part of the search for novel lignan compounds from Magnoliaceae with potential pharmacological activity and with chemotaxonomic interest, the leaves of Manglietia garrettii CRAIB (Thai name montha doi) grown in the temperate house of the botanical garden in Graz were phytochemically examined. In addition to the four known neolignans magnolol, honokiol, 5′-methylhonokiol, and obovatol two new isomeric neolignans, garrettilignan A and garrettilignan B, were isolated from the dichloromethane extract and their structures were determined by NMR spectroscopy and MS. Each of the two new compounds comprised 54 carbon atoms in six phenyl propane units, three terminal 4-allylphenol subunits, two 4-allyl-1,2,6-trihydroxyphenyl subunits together with a 4-trihydroxypropyl-1,2,6-trihydroxyphenol. As five subunits were connected via arylether bridges, a constitutional analysis with HMBC experiments was not possible. Instead, a combination of chemical modification (acetylation), which revealed the positions of three phenolic hydroxyl groups, HMBC and selective NOE experiments was used to determine the connections of the subunits in garrettilignans A and B. Common feature of both compounds is a core built up of two obovatol units, one of them is substituted by two additional 4-allylphenol moieties. The difference between these isomeric compounds is found in the linkage of the two obovatol units. In conclusion, garrettilignans A and B belong to the rare class of substituted dineolignans.

The Norepinephrine (=noradrenaline) transporter (NET) belongs besides serotonin and dopamine transporters to the family of monoamine transporters, regulating the re-uptake of norepinephrine released from neurons [1]. Several drugs binding to the norepinephrine transporter have been utilized therapeutically for the treatment of various disorders of the central (CNS) and peripheral nervous system (PNS), or cardiovascular disorders. In particular, norepinephrine re-uptake inhibitors are useful drugs in the therapy of depression, attention deficit disorder, obsessive compulsive disorder and panic disorder.

The genus Jacaranda (Bignoniaceae) native to the New World, but also widely cultivated in the Old World, contains 49 species. Recently, a review of the ethnobotanical and pharmacological uses of Jacaranda species has pointed out interesting biological and chemical perspectives with regard to skin illnesses and protozoa related diseases [1]. In our current project on the validation of anti-protozoal activity of plants traditionally used in Ecuador, the dichloromethane extract of the leaves of Jacaranda glabra (DC.) Bureau & Schumann has shown promising activity against Plasmodium falciparum K1 strain. Activity guided isolation yielded 4 novel glucosidic esters (1–4) containing quinolacetic acid (R1 ), phenylacetic acid (R2 ) and para-hydroxy-phenylacetic acid (R3 ) moieties. The compounds identified by NMR experiments and MS techniques exhibited activity against Pl. f. K1 strain (IC50 1: 1.1, 2: 0.6, 3: 0.6 and 4 0.5µg/mL) and low cytotoxicity on L-6 cells, except for compound 1 (IC50 1: 2.6, 2: >90, 3: 87 and 4 85µg/mL). In addition, 4 ethnobotanical preparations were found active. Similar structures have been previously reported in literature [2,3].

Traditional Chinese medicine (TCM) has been using about 1300 plants for anti-inflammatory purposes. Activity guided isolation in a medium throughput approach has resulted in the discovery of a number of new drug leads. From the fruits of Evodia rutaecarpa (Juss.) Benth. (Rutaceae), several quinolinone alkaloids, like 1-methyl-2-nonyl-4(1H)-quinolinone, 1-methyl-2-(6Z)-6-undecenyl-4(1H)-quinolinone, 1-methyl-2-(4Z,7Z)-4,7-tridecadienyl-4(1H)-quinolinone, evo-carpine and 1-methyl-2-(6Z,9Z)-6,9-pentadecadienyl-4(1H)-quinolinone, have been isolated which showed strong inhibitory activity on leukotriene biosynthesis in human polymorphonuclear granulocytes [1]. They showed no cytotoxic activity and might bind to the lipid binding site of 5-LOX [2]. Moreover they were very effective against mycobacteria [3]. From Centipeda minima (L.) A. Braun & Asch. (Asteraceae) a series of sesquiterpene lactones, like 6-O-methylacrylplenolin, 6-O-angeloylplenolin and 6-O-tigloyl-plenolin, have been isolated, which exhibited strong inhibitory properties on inducible nitric oxide synthase (iNOS) in RAW 264.7 macrophages [4]. Extracts from Chinese herbs have shown inhibitory properties on expression of NF-kB1 in THP-1 cells [5]. Overexpression of this transcription factor is associated with inflammatory diseases, like rheumatoid arthritis, atherosclerosis, asthma and inflammatory bowel disease. Sesquiterpenes, like parthenolide and helenalin have been demonstrated to be responsible for that effect [6]. Acknowledgements: Part of the work has been supported by Zukunftsfonds Styria (“TCM Research Center Graz”). References: [1] Adams M, et al. (2004) Planta Med. 70: 904–908. [2] Adams M, et al. (2007) Planta Med. 73: 1554–1557. [3] Adams M, et al. (2005) Int. J. Antimicrob. Agents 26(3): 262–264. [4] Fischer M, et al. (2009) in preparation. [5] Gusenleitner S, Bauer R, (2007) Planta Med. 73: 844. [6] Gusenleitner S, et al. (2009) in preparation.

Sesquiterpene lactones (SL) are secondary plant metabolites very widespread in the family of Asteraceae: helenalin from Arnica montana L. or parthenolide from Tanacetum parthenium L. Schultz-Bip. are just two examples.

In Croatia, two indigenous species of the Berberis L. genus, common barberry (B. vulgaris L.) and Croatian barberry (B. croatica Horvat), occur. While common barberry is a well known species growing in many parts of Europe, Croatian barberry is endemic to the illyric-balcanic region (Croatia, Bosnia and Herzegovina, Montenegro, and FYROM) [1]. As a contribution to chemotaxonomy, differences of RP-HPLC chromatograms of B. croatica and B. vulgaris were investigated. Herbal samples were collected at six different locations (three locations per species) in Croatia. Methanolic extracts of roots, twigs, leaves and fruit were analysed with regard to their berberine content and chromatographic fingerprints. The HPLC conditions were: isocratic (TEA-adjusted 0.02 mol L-1H3PO4 (pH 4.82)–acetonitrile (75:25)) and gradient elution (H2O/HCOOH, 9:1 followed by acetonitrile/HCOOH). Signals were detected at 205.4, 254.2 and 330.2nm. Cluster analysis (UPGMA) was employed for evaluation of fingerprints. The average quantity of berberine in extracts of B. vulgaris was higher than in extracts of B. croatica. In extracts of roots it ranged from 7.85 to 12.19% and from 2.44 to 7.29%, for B. vulgaris and B. croatica, respectively. The quantity of berberine in extracts of twigs varied from 0.82 to 1.53% and from 0.48 to 0.63%, for B. vulgaris and B. croatica, respectively. Even though differences in the individual chromatograms of two species could be noted and UPGMA tended to group samples of the same species together, cluster analyses of fingerprints did not reveal important differences between the two species. This finding indicates that common and Croatian barberry are probably very closely related.

Leishmaniasis is a disease caused by an intracellular parasite of the genus Leishmania, which is transmitted to humans by sand-flies. This illness is common in 88 tropical countries around the world with an annual incidence of 1–1.5 million cases and one of its clinical forms, visceral leishmaniasis, is the second largest parasitic killer in the world [1].

In the present investigation the secondary metabolites of Hypericum mutilum L. (Clusiaceae, sect. Trigynobrathys), a native plant of Eastern North America, were studied. In an antibacterial screening against gram-positive and gram-negative bacteria, the dichloromethane extract of H. mutilum was found to exhibit a strong inhibitory activity against Staphylococcus aureus and St. epidermidis in the disk diffusion assay. During the phytochemical analysis, several phloroglucinol derivatives carrying these strong antibacterial activities were isolated and structurally elucidated. Among these, the known uliginosins A and B (1) together with a hitherto unknown phloroglucinol of isouliginosin type (2) were found. Uliginosin A and B showed at a concentration of 10µg considerable activity against the methicillin-resistant St. aureus MRSA NCTC 10442 PVL (-) with inhibition zones of 1.5 and 5mm, respectively.

The hexane, dichloromethane and methanol extracts of 13 plant taxa from Ecuador (200µg/mL) were tested against the human pathogenous bacteria Staphylococcus aureus (ATCC 25923), Bacillus subtilis (Laboratory strain) and Candida albicans (ATCC 10028). Antibacterial activity of the samples was assayed using the agar diffusion method.1

The genus Magnolia plays a role in Asian medicinal systems as TCM and Japanese Kampo medicine [1]. One main lignan constituent in the seeds of the North American Magnolia grandiflora is 4'-O-methyl-honokiol (1) which is known to possess anti-inflammatory activities with COX-2 inhibitory activity (IC50) of 1.5µg/mL. Honokiol – another lignan component of Magnolia species – is active in the same range.

The inhibition of the inducible nitric oxide synthase (iNOS) turned out to be an important aspect in the field of anti-inflammatory research. Overproduction of nitric oxide (NO) induced by the enzymatic activity of iNOS in various cell types plays a role in several inflammatory and also immunoregulatory processes. [1]