Search

Abstract: Ethnopharmacological relevance: Our study shows that large parts of Vanuatu''s medicinal flora remain unexplored and that a high variability of medicinal plant knowledge between islands exists. Aim of the study: The following questions are comparatively analyzed for three islands of Vanuatu: who are the medicinal plant specialists and how important is their knowledge today? Which plants are used to treat common diseases? Materials and methods: On Loh, Ambrym and Aneityum plant related information was collected using semi-structured interviews, transect walks and participant observation. A total of 29 medicinal plant specialists were interviewed. Results: Medicinal plant specialists are either peasants or people with a high rank in the local social system such as members of the chief''s family or priests. Their knowledge may be very broad (Loh, Aneityum) or specialized on specific diseases (Ambrym). Medicinal plant knowledge is transmitted family and gender specific (Loh) or gender and family independent (Ambrym and Aneityum). Overall, 133 medicinal plant species were documented of which 117 are new to Vanuatu''s ethnopharmacopoeia. Mainly members of the Euphorbiaceae and Fabaceae, followed by Asteraceae, Convolvulaceae, Moraceae and Zingiberaceae are utilized. The majority of documented species are trees (33%), followed by herbs (22%) and shrubs (21%). Leaves accounted for the highest number of use reports (43%). The highest diversity of medicinal plants is found for the most common diseases such as skin, gastrointestinal, respiratory system and urogenital system diseases. Only a small overlap of taxa between the islands was found. Conclusions: The biocultural diversity of Vanuatu is reflected in the variability of medicinal plant knowledge and differences in the traditional medicinal system between the three islands investigated. Traditional medicine is more vital on remote islands. The better connected the islands are to the main city, the more dominant western medicine becomes and traditional medicine mainly remains to treat illnesses with a magical origin. [Copyright &y& Elsevier]

Abstract: From the aerial parts of Marrubium velutinum and Marrubium cylleneum, seven labdane diterpenes, velutine A, 15-epi-velutine A, velutine B, 15-epi-velutine B, velutine C, cyllenine A and 15-epi-cyllenine A, have been isolated together with five known diterpenes and four known flavones. The structures of the isolated compounds were established by means of NMR [1H–1H–COSY, 1H–13C–HMQC, HMBC, HMQC–TOCSY, NOESY] and MS spectral analyses. Complete NMR assignments are reported for known compounds. [Copyright &y& Elsevier]

Myrrh has a long tradition in the treatment of inflammatory diseases. However, many of its (active) constituents are still unknown. In the present study, secondary metabolites were isolated from an ethanolic extract by various separation methods (liquid–liquid partition, silica and RP18 flash chromatography, CPC, and preparative HPLC), their structures were elucidated with NMR spectroscopy and mass spectrometry, and the selected compounds were tested for their effect on LPS-induced NO production by RAW 264.7 murine macrophages. Among the isolated substances are 17 sesquiterpenes (1–17) including the first 4,8-cycloeudesmane (1), a triterpene (38), two phytosterols (39, 40) and one lignan (43), which were previously unknown as natural products. Numerous compounds are described for the first time for the genus Commiphora. Eight of the eleven compounds tested (1, 29, 31, 32, 34–37) showed a statistically significant, concentration-dependent weak to moderate anti-inflammatory effect on NO production in the LPS-stimulated RAW 264.7 macrophages in vitro. For the reference substance, furanoeudesma-1,3-diene, an IC50 of 46.0 µM was determined. These sesquiterpenes might therefore be part of the multi-target molecular principles behind the efficacy of myrrh in inflammatory diseases. [ABSTRACT FROM AUTHOR]

The phytochemical studies on the aerial parts of Sideritis dichotoma led to the isolation and identification of a new iridoid glycoside (1), along with four known iridoid glycosides (2 - 5), three phenylethanoid glycosides (6 – 8), two flavone glycosides (9 and 10), one neolignan (11) and a megastigmane glycoside (12). Their structures were elucidated by spectroscopic techniques. Compounds 2 , 3 and 12 have never been found in the Sideritis genus before. Furthermore, eleven compounds (1 – 5 , 7 – 12) were characterized for the first time from S. dichotoma. The chemotaxonomic importance of isolated compounds was discussed. This is the first phytochemical study on the polar constituents of S. dichotoma , an endemic species to Türkiye. [Display omitted] • A new iridoid glycoside (1) was obtained from Sideritis dichotoma. • Compounds 2 , 3 and 12 were isolated from the genus Sideritis for the first time. • First report on the existence of a megastigmane glycoside in the genus Sideritis. • All compounds are reported for the first time from S. dichotoma , but for 6. [ABSTRACT FROM AUTHOR]

Abstract One new diarylheptanoid (1) and one previously unknown ascorbic acid derivative (2) along with 48 known compounds including three ascorbic acid derivatives (3-5), three diarylheptanoids (6-8), three juglone derivates (9-11), six racemic α -tetralones (12a/b-17a/b), four anthraquinones (18-21), eight flavonoids (22-29), nine oligomeric proanthocyanidins (30-38), one phenolic aldehyde (39), one aromatic ketone (40), one pyrrole alkaloid (41), one steroid (42), six terpenes (43-48) and two fatty acids (49-50) were isolated from the leaves of Juglans regia. Their chemical structures were elucidated on basis of 1D and 2D NMR techniques, HRESIMS, polarimetry and CD spectroscopy as well as chiral HPLC and literature data. Furthermore, the chemotaxonomic significance is discussed. Highlights • 50 secondary metabolites were isolated from Juglans regia leaves. • Unknown diarylheptanoid and ascorbic acid derivatives were isolated. • One pyrrole alkaloid was isolated for the first time from the Juglandaceae. • Phenyldilactones were isolated for the first time from the Juglandaceae. [ABSTRACT FROM AUTHOR]

Flavonoids, proanthocyanidins (PAs) and salicylic alcohol derivatives are the main groups of ingredients in Salix needed as defensive tools and signal molecules, but have also pharmaceutical importance. The present study investigated total PA content, complete PA pattern, the oligomeric/total PAs quotient and the contents of catechin and epicatechin during one growing-season for the leaves and this year's sprouts in ten willows ( Salix pentandra L. ♂, S . alba L. ♂, S. fragilis L. ♀, S. caprea L. ♂ & ♀, S. cinerea L. ♂, S. caprea x cinerea ♂, S. daphnoides Vill. ♂ & ♀ and S. purpurea L. ♀; all Salicaceae). Comparison of the different species revealed distinct seasonal fluctuations of the oligomeric and polymeric PA fractions, but the contents of both groups always developed in the same direction. All willows prefer the synthesis of PAs with DP-2 - DP-4 within the oligomeric fraction (DP-2 – DP-10) and species with rather low PA contents like S. purpurea (0.1–2.6 mg/g) as well as species with rather high PA contents like S. alba (3.8–14.7 mg/g) were found. Only slight gender specific differences could be observed for both sexes of S. daphnoides and S. caprea. The PA pattern of the hybrid S. caprea x cinerea seems to be influenced by both parents. Thus, the accumulation of the oligomeric PAs accorded to S. caprea and the polymeric PAs matched S. cinerea resulting in an overall depression of PAs in the sprouts and a varying seasonal trend in the leaves. In contrast, the content of catechin remained high and seemed to be not influenced in the hybrid. Although only one individual of each Salix species could be considered in this screening study, the present results demonstrate the variability of the flavan-3-ol pattern within the genus Salix but also some preliminary correlations could be observed. Future studies with more Salix species will provide more insights into chemotaxonomic correlations. [ABSTRACT FROM AUTHOR]

A methanolic extract of Morella salicifolia bark was fractionated by various chromatographic techniques yielding six previously unknown cyclic diarylheptanoids, namely, 7-hydroxymyricanol 5-O-β-d-glucopyranoside (1), juglanin B 3-O-β-d-glucopyranoside (2), 16-hydroxyjuglanin B 17-O-β-d-glucopyranoside (3), myricanone 5-O-β-d-gluco-pranosyl-(1→6)-β-d-glucopyranoside (4), neomyricanone 5-O-β-d-glucopranosyl-(1→6)-β-d-glucopyranoside (5), and myricanone 17-O-α-l-arabino-furanosyl-(1→6)-β-d-glucopyranoside (6), respectively, together with 10 known cyclic diarylheptanoids. The structural diversity of the diarylheptanoid pattern in M. salicifolia resulted from varying glycosidation at C-3, C-5, and C-17 as well as from substitution at C-11 with hydroxy, carbonyl or sulfate groups, respectively. Structure elucidation of the isolated compounds was achieved on the basis of one- and two-dimensional nuclear magnetic resonance (NMR) as well as high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS) analyses. The absolute configuration of the glycosides was confirmed after hydrolysis and synthesis of O-(S)-methyl butyrated (SMB) sugar derivatives by comparison of their 1H-NMR data with those of reference sugars. Additionally, absolute configuration of diarylheptanoid aglycones at C-11 was determined by electronic circular dichroism (ECD) spectra simulation and comparison with experimental CD spectra after hydrolysis. [ABSTRACT FROM AUTHOR]

A methanolic extract of Juglans regia L. leaves was fractioned by various chromatographic techniques yielding a total of 40 metabolites belonging to megastigmane, tetralone, phenylpropanoid, neolignane and juglone glycosides. Ten unknown megastigmane glucoside derivatives (juglanionosides A-K, 1 – 10 ) and six unknown tetralone glucoside derivatives (juglanosides J-O, 11 – 16 ) together with 24 known compounds - among them 16 described for the first time in Juglans - were isolated. As characteristic structural feature, the previously undescribed compounds showed acylation of the sugar units with sinapic, ferulic, coumaric, benzoic or salicylic acid. Their chemical structures were elucidated on the basis of 1D and 2D NMR techniques, HRESIMS as well as CD spectroscopy. Absolute stereochemistry was revealed by mild alkaline hydrolysis and comparison of CD and polarimetric data to literature values. [ABSTRACT FROM AUTHOR]

Objectives G protein coupled receptor (GPCR)-G α fusion proteins are often employed to investigate receptor/G protein interaction. In this study, the impact of G α fusion proteins on pharmacology of CBRs, both mediating signals through G αi proteins, were investigated. G αi2 was fused to the C-terminus of the CBRs or co-expressed with non-fused G αi2 in Sf9 cells, always together with G β1 γ2. Furthermore, the impact of RGS proteins on CBR signaling in combination with the CBR fusion approach was examined, using RGS4 and RGS19 as paradigms. Methods CBR ligands were characterized in the steady-state GTPase assay and pharmacological properties of ligands in the different test systems were correlated. Key findings Fusion of CBRs to G αi2 enhanced the maximal stimulatory effects of ligands compared to the co-expression system, especially for CB2R. RGS4, but not RGS19, behaved as a GTPase-activating protein at CBRs in the G αi2 co-expression and fusion system. Fusion of GPCR, most prominently CB2R, to G αi2, and co-expression with RGS4 altered the pharmacological properties of ligands. Conclusions Our data suggest that fusion of CB2R to G αi2 and co-expression with RGS4 impedes with conformational changes. Moreover, our results support the concept of ligand-specific receptor conformations. Finally, this paper describes the most sensitive CBR test system currently available. [ABSTRACT FROM AUTHOR]

The oleo–gum resin of Commiphora myrrha (Nees) Engl. has a long history of medicinal use, although many of its constituents are still unknown. In the present investigation, 34 secondary metabolites were isolated from myrrh resin using different chromatographic techniques (silica flash chromatography, CPC, and preparative HPLC) and their structures were elucidated with NMR spectroscopy, HRESIMS, CD spectroscopy, and ECD calculations. Among the isolated substances are seven sesquiterpenes (1–7), one disesquiterpene (8), and two triterpenes (23, 24), which were hitherto unknown, and numerous substances are described here for the first time for C. myrrha or the genus Commiphora. Furthermore, the effects of selected terpenes on cervix cancer cells (HeLa) were studied in an MTT-based in vitro assay. Three triterpenes were observed to be the most toxic with moderate IC50 values of 60.3 (29), 74.5 (33), and 78.9 µM (26). Due to the different activity of the structurally similar triterpenoids, the impact of different structural elements on the cytotoxic effect could be discussed and linked to the presence of a 1,2,3-trihydroxy substructure in the A ring. The influence on TNF-α dependent expression of the intercellular adhesion molecule 1 (ICAM-1) in human microvascular endothelial cells (HMEC-1) was also tested for 4–6, 9–11, 17, 18, 20, and 27 in vitro, but revealed less than 20% ICAM-1 reduction and, therefore, no significant anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

Within the large family of Dioscoreaceae, Dioscorea communis (L.) Caddick & Wilkin (syn. Tamus communis L.) is considered among the four most widespread representatives in Europe, and it is commonly known under the name black bryony or bryonia. To date, reports have revealed several chemical components from the leaves and tubers of this plant. Nevertheless, an extensive phytochemical investigation has not been performed on its berry juice. In the present study, metabolite profiling procedures, using LC-MS, GC-MS, and NMR approaches, were applied to investigate the chemical profile of the D. communis berries. This work reveals the presence of several metabolites belonging to different phytochemical groups, such as fatty acid esters, alkylamides, phenolic derivatives, and organic acids, with lactic acid being predominant. In parallel, based on orally transmitted traditional uses, the initial extract and selected fractions were tested in vitro for their antibacterial effects and exhibited good activity against two bacterial strains related to skin infections: methicillin-resistant Staphylococcus aureus and Cutibacterium acnes. The MIC and MBC values of the extract were determined at 1.56% w/v against both bacteria. The results of this study provide important information on the chemical characterization of the D. communis berry juice, unveiling the presence of 71 metabolites, which might contribute to and further explain its specific antibacterial activity and its occasional toxicity. [ABSTRACT FROM AUTHOR]

Abstract: A set of hybrid molecules were synthesized out of lipoic acid, α,ω-diamines of different lengths serving as spacers, and cholinesterase (ChE) inhibiting [2,1-b]quinazolinimines. Depending on the length of the alkylene spacer the amide hybrids are inhibitors of acetylcholinesterase (AChE) with inhibitory activities of 0.5–4.6μM and inhibitors of butyrylcholinesterase (BChE) with activities down to 5.7nM, therefore greatly exceeding the inhibitory activities of the parent quinazolinimines by factors of up to 1000. Due to increasing activity at BChE with increasing length of the alkylene spacer ∼100-fold selectivity toward BChE is reached with a hepta- and an octamethylene spacer. Kinetic measurements reveal competitive and reversible inhibition of both ChEs by the hybrids. Furthermore, cell viability and antioxidant activity (using the ORAC-fluorescein assay) of several hybrids were evaluated, showing cytotoxicity at concentrations from 3.7 to 10.2μM and antioxidant properties are in the range of 0.4–0.8 Trolox equivalents (lipoic acid=0.6). [Copyright &y& Elsevier]

Abstract: As immunocompetent cells of the brain, microglia are able to counteract the damaging effects of amyloid-β in Alzheimer''s disease by phagocytosis-mediated clearance of protein aggregates. The survival and health of microglia are therefore critical for attenuating and preventing neurodegenerative diseases. In a microglial cell line pretreated with St. John''s wort (Hypericum perforatum L.) extract (HPE), the cell death evoked by treatment with amyloid-β (25–35) and (1–40) was attenuated significantly in a dose-dependent manner. Investigation of the single compounds in the extract revealed that the flavanols (+)-catechin and (−)-epicatechin increase cell viability slightly, whereas the flavonol quercetin and its glycosides rutin, hyperosid and quercitrin showed no effect on cell viability. In contrast, at the same concentration, the flavonoids reduced the formation of amyloid-induced reactive oxygen species in microglia, indicating that improvement of cell viability by the catechins is not correlated to the antioxidant activity. No influence of HPE on the capacity of microglia to phagocytose sub-toxic concentrations of fibrillar amyloid-β (1–40) was observed. Other experiments showed that HPE, (+)-catechin and (−)-epicatechin can alter cellular membrane fluidity and thereby may have a beneficial effect on cell health. Our findings provide in vitro evidence that treatment especially with the complex plant extract HPE may restore or improve microglial viability and thereby attenuate amyloid-β mediated toxicity in Alzheimer''s disease. [Copyright &y& Elsevier]

Abstract: Three iridoid glycosides, 6′-O-E-p-coumaroylgardoside (1), 6′-O-p-E-coumaroyl-8-epi-loganic acid (2) and scutelloside (3) were isolated from the aerial parts of Scutellaria albida subsp. albida, in addition to an anomeric mixture in equilibrium of one iridoid aglycone (4, 4a), nine iridoid glycosides (5–13), four known phenylethanoid glycosides (14–17), and six known phenolic derivatives (18–23). [Copyright &y& Elsevier]

From the aerial parts of Marrubium velutinum, one acylated flavonoid glycoside, chrysoeriol 7-O-(3″,6″-di-O-E-p-coumaroyl)-β-d-glucopyranoside, and two tetrasaccharidic phenylethanoid glycosides, velutinosides I-II, have been isolated together with ten known flavonoids and seven known phenylethanoid glycosides. The structures of the isolated compounds were established by means of NMR, MS, and UV spectral analyses. [Copyright &y& Elsevier]

Curcumin, the yellow pigment of the rhizome of Curcuma longa is known to inhibit the transcription factors AP-1, Egr-1, NF-κB, c-myc and several important signaling kinases. We therefore investigated the differential effects of curcumin in concentation between 1.5 and 13.6 μM on gene expression in T Jurkat CD4+ and human peripheral blood mononuclear cells (PBMCs). Relative quantification with reverse transcription real-time PCR (RT-rt-PCR) showed that low concentrations of curcumin significantly down-regulated mitogen-induced granulocyte macrophage colony stimulating factor (GM-CSF) mRNA (3- to 5-fold at 3 μM) in a dose- and time-dependent manner in both cell types. In comparison, the down-regulation of inducible nitric oxide (iNOS) mRNA levels was less pronounced, but interferon gamma (IFN-γ) mRNA was dose-dependently up-regulated with curcumin concentrations up to 8.2 μM. Cyclin D1 mRNA expression was specifically inhibited in Jurkat T cells and stimulated PBMCs. The transcription factors NF-κB and NF-ATc were not affected in PBMCs. Interleukin-2 (IL-2), and-6 (IL-6) mRNAs levels were not influenced markedly by curcumin in stimulated PBMCs, but significantly reduced in stimulated Jurkat T cells. In addition, cytotoxic effects and down-regulation of mRNAs, including p65 and the house-keeping genes could only be measured in Jurkat T cells. These findings confirm previous reports on the anti-neoplastic potential of curcumin and show that this compound differentially modulates the expression profile of Th1 cells and PBMCs. [Copyright &y& Elsevier]

Several medical plants belonging to the genera Passiflora, Viola, and Crataegus accumulate flavonoid C-glycosides, which likely contribute to their efficacy. Information regarding their phase I and II metabolism in the liver are lacking. Thus, in vitro liver metabolism of orientin, isoorientin, schaftoside, isoschaftoside, vitexin, and isovitexin, all of which accumulated in Passiflora incarnata L., was investigated by incubation in subcellular systems with human liver microsomes and human liver S9 fraction. All metabolite profiles were comprehensively characterized using HPLC-DAD and UHPLC–MS/MS analysis. Mono-glycosylic flavones of the luteolin-type orientin and isoorientin showed a broad range of mono-glucuronidated and mono-sulfated metabolites, whereas for mono-glycosylic flavones of the apigenin-type vitexin and isovitexin, only mono-glucuronidates could be detected. For di-glycosylic flavones of the apigenin-type schaftosid and isoschaftosid, no phase I or II metabolites were identified. The main metabolite of isoorientin was isolated using solid-phase extraction and prep. HPLC-DAD and identified as isoorientin-3′-O-α-glucuronide by NMR analysis. A second isolated glucuronide was assigned as isoorientin 4′-O-α-glucuronide. These findings indicate that vitexin and isovitexin are metabolized preferentially by uridine 5′-diphospho glucuronosyltransferases (UGTs) in the liver. As only orientin and isoorientin showed mono-sulfated and mono-glucuronidated metabolites, the dihydroxy group in 3′,4′-position may be essential for additional sulfation by sulfotransferases (SULTs) in the liver. The diglycosylic flavones schaftoside and isoschaftoside are likely not accepted as substrates of the used liver enzymes under the chosen conditions. [ABSTRACT FROM AUTHOR]

Several medical plants, such as Passiflora incarnata L., contain C-glycosylated flavonoids, which may contribute to their efficacy. Information regarding the bioavailability and metabolism of these compounds is essential, but not sufficiently available. Therefore, the metabolism of the C-glycosylated flavones orientin, isoorientin, schaftoside, isoschaftoside, vitexin, and isovitexin was investigated using the Caco-2 cell line as an in vitro intestinal and epithelial metabolism model. Isovitexin, orientin, and isoorientin showed broad ranges of phase I and II metabolites containing hydroxylated, methoxylated, and sulfated compounds, whereas schaftoside, isoschaftoside, and vitexin underwent poor metabolism. All metabolites were identified via UHPLC-MS or UHPLC-MS/MS using compound libraries containing all conceivable metabolites. Some structures were confirmed via UHPLC-MS experiments with reference compounds after a cleavage reaction using glucuronidase and sulfatase. Of particular interest is the observed cleavage of the C–C bonds between sugar and aglycone residues in isovitexin, orientin, and isoorientin, resulting in unexpected glucuronidated or sulfated luteolin and apigenin derivatives. These findings indicate that C-glycosidic flavones can be highly metabolized in the intestine. In particular, flavonoids with ortho-dihydroxy groups showed sulfated metabolites. The identified glucuronidated or sulfated aglycones demonstrate that enzymes expressed by Caco-2 cells are able to potentially cleave C–C bonds in vitro. [ABSTRACT FROM AUTHOR]

Thirteen compounds were isolated from the aerial parts of Hypericum kelleri B ald ., growing as an endemic on the island of Crete (Greece). These compounds comprise four previously unknown prenylated xanthones 1,2-dihydro-3,8-dihydroxy-6-methoxy-1,1,5-tri(3-methylbut-2-enyl)xanthen-2,9-dione (kellerine A), 1,2-dihydro-3,6,8-trihydroxy-1,1,5-tri(3-methylbut-2-enyl)xanthen-2,9-dione (kellerine B), 1,2-dihydro-3,8-dihydroxy-6-methoxy-1,1-bi(3-methylbut-2-enyl)xanthen-2,9-dione (6-methylpatulone), ( R / S )-1,3,5-trihydroxy-2-(3-methyl-2-buten-1-yl)-4-[2-(3-methylbut-2-enyl)-3-methylbut-3-enyl]-6-methoxy-9H-xanthen-9-one ((2″ R / S )-kellerine C) and the hitherto undescribed depsidone ( R / S )-1,3,6-trihydroxy-5-methoxy-2-(3-methyl-2-buten-1-yl)-4-[2-(3-methylbut-2-enyl)-3-methylbut-3-enyl]-11Η-dibenzo[b,e] [1,4]dioxepin-9-one ((2″ R / S )-creticine). As known compounds, brevipsidone D, 4-geranyl-2-(2′-isobutyryl)-phloroglucinol, 4-geranyl-2-(2′-methylbutyryl)-phloroglucinol, I3, II8-biapigenin, quercetin, avicularin, pseudohypericin and neochlorogenic acid have been isolated. The structures were elucidated on the basis of their 1D, 2D NMR, CD and MS data. The study confirms the typical occurrence of xanthones in Hypericum section Oligostema (B oiss .) S tef. , and is also the first report on the simultaneous isolation of acylphloroglucinols in this section. Furthermore the first evidence of depsidones in the genus Hypericum L. is reported. Cytotoxicity was investigated in HeLa cells for prenylated xanthones and the depsidones. Both triprenylated 1,2-dihydroxanthones (kellerine A and B) showed significant in vitro cytotoxicity with IC 50 values of 2.5 ± 0.1 (kellerine A) and 5.9 ± 0.9 (kellerine B) μM, whereas other compounds were less cytotoxic (IC 50 > 20 μM). [ABSTRACT FROM AUTHOR]

Recently, a new class of Ionic Liquids based on oligoether carboxylates was introduced by our research group. This CO ncept of M elting P oint L owering due to ET hoxylation (COMPLET) is now extended to cationic ammonium-based surfactants as counterions. The common requirement of a bulky headgroup for ionic liquid character is superseded by the presence of high flexibility in the molecular structure of the anion. These new salts of the 2,5,8,11-Tetraoxatridecan-13-oate acid (TOTOA) form room temperature Ionic Liquids up to a chain length of twelve carbon atoms of the ammonium ion. Viscosities even lower than those of the quaternary ammonium salts and conductivities in the range of the alkali salts are found. Results are discussed in terms of ion-pairing concepts as well as considering the possible complexation ability of the TOTO ion. This idea facilitates the conception of surfactant-like Ionic Liquids with a significantly improved eco-index, in terms of cytotoxicity and biodegradability, compared to classical/common systems. [ABSTRACT FROM AUTHOR]

Recently, a new class of Ionic Liquids based on oligoether carboxylates was introduced by our research group. This CO ncept of M elting P oint L owering due to ET hoxylation (COMPLET) is now extended to cationic ammonium-based surfactants as counterions. The common requirement of a bulky headgroup for ionic liquid character is superseded by the presence of high flexibility in the molecular structure of the anion. These new salts of the 2,5,8,11-Tetraoxatridecan-13-oate acid (TOTOA) form room temperature Ionic Liquids up to a chain length of twelve carbon atoms of the ammonium ion. Viscosities even lower than those of the quaternary ammonium salts and conductivities in the range of the alkali salts are found. Results are discussed in terms of ion-pairing concepts as well as considering the possible complexation ability of the TOTO ion. This idea facilitates the conception of surfactant-like Ionic Liquids with a significantly improved eco-index, in terms of cytotoxicity and biodegradability, compared to classical/common systems. [ABSTRACT FROM AUTHOR]

The alkaloid rutaecarpine and its derivatives have been described as cytotoxic and hold potential as antitumor agents. Nevertheless, their synthesis is demanding and compounds display poor water solubility. Herein, we describe the synthesis of two sets of rutaecarpine derivatives with amine functions to improve solubility. Using a classic shake-flask experiment and a potentiometric titration platform, the water solubility of the compounds was determined. Solubility improved significantly with the amine functions connected over the indole- N atom. Reduction of metabolic activity and cell viability on HeLa cells was in the same range or better for these derivatives compared to the chemically unaltered parent compounds prepared in a new synthetic procedure established in our group. [ABSTRACT FROM AUTHOR]

Isosorbide-2-carbamates-5-aryl esters are highly potent and very selective butyrylcholinesterase inhibitors. The objective of the present work was to address the hypothesis that the isosorbide-aryl-5-ester group could be replaced with an antioxidant functionality while maintaining inhibitor effects and selectivity. We successfully incorporated ferulic acid or lipoic acid groups producing potent selective inhibitors of butyrylcholinesterase (BuChE). The hybrid compounds were non-toxic to the murine hippocampal cell line HT-22 and lipoate esters were neuroprotective at 10 and 25 μM when the cells were challenged with glutamate (5 mM) in a similar manner to the positive control quercetin. The benzyl carbamate 7a was a potent inhibitor of BuChE (IC50 150 nM) and it was effective in reducing glutamate toxicity to neuronal cells at >5 μM. Representative compounds exhibited an antioxidant effect in the oxygen radical absorbance capacity assay as the lipoate 7d was not active, whereas the ferulate 8a showed a weak, but significant, activity with 0.635 ± 0.020 Trolox Equivalent. [ABSTRACT FROM AUTHOR]

Butyrylcholinesterase (BChE) is a promising target for the treatment of later stage cognitive decline in Alzheimer's disease. A set of pseudo-irreversible BChE inhibitors with high selectivity over hAChE was synthesized based on carbamates attached to tetrahydroquinazoline scaffolds with the 2-thiophenyl compound 2p as the most potent inhibitor of eqBChE (KC = 14.3 nM) and also of hBChE (KC = 19.7 nM). The inhibitors transfer the carbamate moiety onto the active site under release of the phenolic tetrahydroquinazoline scaffolds that themselves act as neuroprotectants. By combination of kinetic data with molecular docking studies, a plausible binding model was probed describing how the tetrahydroquinazoline scaffold guides the carbamate into a close position to the active site. The model explains the influence of the carrier scaffold onto the affinity of an inhibitor just before carbamate transfer. This strategy can be used to utilize the binding mode of other carbamate-based inhibitors. [ABSTRACT FROM AUTHOR]

The proazulene matricine ( 1 ) is present in chamomile flower heads and has been proven to exhibit strong in vivo anti-inflammatory activity. In contrast to other secondary metabolites in chamomile preparations like its degradation product chamazulene ( 2 ), no plausible targets have been found to explain this activity. Therefore we revisited 1 regarding its in vitro anti-inflammatory activity in cellular and molecular studies. Using ICAM-1 as a marker for NF-κB activation, it was shown that ICAM-1 protein expression induced by TNF-α and LPS, but not by IFN-γ, was remarkably inhibited by 1 in endothelial cells (HMEC-1). Inhibition was concentration-dependent in a micromolar range (10–75 μM) and did not involve cytotoxic effects. At 75 μM expression of the adhesion molecule ICAM-1 was down to 52.7 ± 3.3% and 20.4 ± 1.8% of control in TNF-α and LPS-stimulated HMEC-1, respectively. In contrast, 2 showed no activity. Quantitative RT-PCR experiments revealed that TNF-α-induced expression of the ICAM-1 gene was also reduced by 1 in a concentration-dependent manner, reaching 32.3 ± 6.2% of control at 100 μM matricine. Additional functional assays (NF-κB promotor activity and cytoplasm to nucleus translocation) confirmed the inhibitory effect of 1 on NF-κB signaling. Despite the fact that 1 lacks an α,β-unsaturated carbonyl and is thus not able to act via a Michael reaction with electron rich SH groups of functional biological molecules, data gave strong evidence that 1 inhibits NF-κB transcriptional activity in endothelial cells by an hitherto unknown mechanism and this may contribute to its well-known anti-inflammatory activity in vivo . [ABSTRACT FROM AUTHOR]

Two series of natural and natural-like mono- and bicyclic acylphloroglucinols derived from secondary metabolites in the genus Hypericum (Hypericaceae) were synthesised and tested in vitro for anti-proliferative and tube-formation inhibitory activity in human microvascular endothelial cells (HMEC-1). In addition, their anti-oxidative activity was determined via an ORAC-assay. The first series of compounds ( 4a – e ) consisted of geranylated monocyclic acylphloroglucinols with varying aliphatic acyl substitution patterns, which were subsequently cyclised to the corresponding 2-methyl-2-prenylchromane derivatives ( 5a and 5d ). The second series involved compounds containing a 2,2-dimethylchromane skeleton with differing aromatic acyl substitution ( 6a – d and 7a – e ). Compound 7a , (5,7-dihydroxy-2,2-dimethylchroman-6-yl)-(3,4-dihydroxyphenyl)methanone), showed the highest in vitro anti-proliferative activity with an IC 50 of 0.88 ± 0.08 μM and a remarkable anti-oxidative activity of 2.8 ± 0.1 TE from the ORAC test. Interestingly, the high anti-proliferative activity of these acylphloroglucinols was not associated with tube-formation inhibition. Compounds ( E )-1-(3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4,6-trihydroxyphenyl)-2-methylbutan-1-one ( 4d ) and (5,7-dihydroxy-2,2-dimethylchroman-6-yl)(3,4-dimethoxyphenyl)methanone ( 6a ) exhibited moderate to weak anti-proliferative effects (IC 50 11.0 ± 1 μM and 48.0 ± 4.3 μM, respectively) and inhibited the capillary-like tube formation of HMEC-1 in vitro , whereas 7a was inactive. The most active compound in the ORAC assay was 7c , which exhibited an anti-oxidative effect of 6.6 ± 1.0 TE. However, this compound showed only weak activity during the proliferation assay (IC 50 53.8 ± 0.3) and did not inhibit tube-formation. [ABSTRACT FROM AUTHOR]

A new acylated flavonol glycoside, namely gomphrenol-3-O-(5'"-O-E-feruloyl)-β-D-apiofuranosyl-(1→2)[β-D-glucopyranosyl-(1→6)]-β-D-glucopyranoside (1) was isolated from the aerial parts of Chenopodium foliosum Asch. The structure of 1 was determined by means of spectroscopic methods (1D and 2D NMR, UV, IR, and HRESIMS). Radical scavenging and antioxidant activities of 1 were established using DPPH and ABTS radicals, FRAP assay and inhibition of lipid peroxidation (LP) in linoleic acid system by the ferric thiocyanate method. Compound 1 showed low activity (DPPH and ABTS) or lack of activity (FRAP and LP). In combination with CCl4, 1 reduced the damage caused by the hepatotoxic agent and preserved cell viability and GSH level, decreased LDH leakage and reduced lipid damage. Effects were concentration dependent, most visible at the highest concentration (100 µg/mL), and similar to those of silymarin. [ABSTRACT FROM AUTHOR]

A series of cyclic acyl guanidine with carbamate moieties have been synthesized and evaluated in vitro for their AChE and BChE inhibitory activities. Structure−activity relationships identified compound 23 as a nanomolar and selective BChE inhibitor, while compound 32 exhibited nanomolar and selective AChE inhibition, selectivity depending on both the structure of the carbamate substituent as well as the position of guanidines- N substitution. The velocity of enzyme carbamoylation was analyzed and showed similar behavior to physostigmine. Phenolic compounds formed after carbamate transfer to the active site of cholinesterases showed additional neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation. [ABSTRACT FROM AUTHOR]

The design of bivalent ligands targeting G protein-coupled receptors (GPCRs) often leads to the development of new, highly selective and potent compounds. To date, no bivalent ligands for the human cannabinoid receptor type 2 (hCB2R) of the endocannabinoid system (ECS) are described. Therefore, two sets of homobivalent ligands containing as parent structure the hCB2R selective agonist 13a and coupled at different attachment positions were synthesized. Changes of the parent structure at these positions have a crucial effect on the potency and efficacy of the ligands. However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists. [ABSTRACT FROM AUTHOR]

Abstract: Two sets of carbamates based on the natural alkaloid evodiamine were designed, synthesized and evaluated as potential butyrylcholinesterase inhibitors. Although a set of carbamates of 3-hydroxyevodiamine (10a–f) is inactive both at AChE and BChE, carbamates of 5-deoxo-3-hydroxyevodiamine (11a–f) exhibit much better potency with selectivity toward BChE. The heptyl carbamate of 5-deoxo-3-hydroxyevodiamine (11c) shows the best potency with an IC50 value of 77 nM and very good selectivity over AChE. ORAC and cell-based assays indicate 11c owns pronounced antioxidant properties with 1.75 Trolox equivalents and strong neuroprotection even from 1 μM onwards. These combined activities might enable compound 11c to be a potential candidate for treatment of Alzheimer's disease. [Copyright &y& Elsevier]

Extracts of Ruscus aculeatus L., known as butcher's broom, are mainly used for the treatment of chronic venous insufficiency (CVI). In a recent study on the phenolic compounds of Rusci rhizoma, new phenyl-1-benzoxepinols were isolated. As the therapeutic effect of butcher's broom is ascribed to the pharmacological activity of the main constituents, steroidal saponins and their aglycones the ruscogenins, the role of the newly identified compounds was of interest. Owing to the low availability of the compounds by isolation, we synthesized them for pharmacological testing. In an ORAC-fluorescein assay they revealed a significant antioxidative activity, which may contribute to the anti-inflammatory properties of the phenolic fraction obtained from Rusci rhizoma extracts. [ABSTRACT FROM AUTHOR]

Phytochemical studies on the leaves of the Philippine endemic Annonaceae plant, Goniothalamus gitingensis enabled the isolation and identification of four secondary metabolites corresponding to three styryllactones, isoaltholactone (1), altholactone (2) and goniopypyrone (3), and the alkaloid liriodenine (4). Structure identification was facilitated through various spectroscopic experiments such as NMR (¹H, 13C, COSY, HSQC, HMBC and NOESY), LR-EIMS, X-ray and through comparison with literature values. Our study accounts the first report of all compounds in this plant species. The extracts together with the isolated compounds (1-4) were tested for antituberculosis activity using MABA and cytotoxic activity using the CellTiter-Blue1 assay. The majority of the samples tested indicated good inhibitory activity against Mycobacterium tuberculosis H37 Rv (MIC up to 16 µg/mL). Liriodenine (4) showed the most excellent antimycobacterial activity (MIC=16 µg/mL) followed by 1 and the 5:4 mixture of 1 and 2. Their cytotoxicity against three human cancer cell lines, human umbilical vein endothelial cell line (HUVEC), human leukemia cell line (K-562) and HeLa cells were also assessed. The crude extract, alkaloid extract, petroleum ether sub-extract and EtOAc sub-extract showed moderate cytotoxicity against the cancer cell-lines. In addition, the results showed that compounds 1, 4 and the mixture of 1 and 2 exhibited highest cytotoxicity against HUVEC, K-562 and HeLa cell lines with CC50 values up to 4 µg/mL (vs. HUVEC and/or K-562) and CC 50 values up to 25.1 µg/mL (vs. HeLa). [ABSTRACT FROM AUTHOR]

AFLP fingerprinting, nrDNA sequencing, and HPLC of phenolic compounds from bark samples was used to assess the intensity of hybridisation in two mixed stands of Salix alba, S. fragilis, and their hybrid S. × rubens (Salicaceae) along the Danube in the vicinity of Regensburg (SE Germany). AFLP analyses of 130 individuals from two mixed and two pure strands of the parental species resulted in a matrix of 337 polymorphic loci that was analysed with Bayesian cluster algorithms implemented in the software programmes Structure and NewHybrids. The results, together with sequence polymorphisms of the nrDNA ITS1 + 5.8S region, indicate that the three taxa are distinctly separated and that only a few F2-hybrids and no backcrosses to the parental species are present in the surveyed mixed stands. These findings were corroborated by HPLC studies of the phenolic compounds from bark samples that were carried out for the same individuals. A multivariate statistical analysis of relative peak areas of chromatograms (PCA, principal component analysis) indicates the clear separation of parental and the intermediate position of S. × rubens individuals. [ABSTRACT FROM AUTHOR]

Abstract: Liver ischemia/reperfusion (I/R) leads to formation of reactive oxygen species (ROS), which cause hepatic injury and initiate an inflammatory response, which is a critical problem after liver surgery and transplantation. Xanthohumol, the major prenylated chalcone found in hops, has been discussed for its anti-inflammatory and ROS-scavenging properties, and thus, we aimed to investigate the effect of xanthohumol in a model of warm I/R liver injury. Xanthohumol was applied to BALB/c mice orally at a dose of 1mg/g body weight for 5days before I/R-injury was induced by clamping the vascular blood supply to the median and left lateral liver lobe for 1h followed by a 6h period of reperfusion. At this time, HPLC analysis revealed hepatic xanthohumol levels of approximately 2μM, a concentration which has been shown to inhibit inflammatory effects in vitro. Assessment of hepatic HMOX1 expression, hepatic glutathione content and immunohistochemical analysis for proteins conjugated with the reactive aldehyde 4-hydroxynonenal indicated that I/R-induced oxidative stress was significantly inhibited in xanthohumol-fed compared to control mice. Histological analysis, TUNEL staining and determination of transaminase serum levels revealed no significant effects of xanthohumol on acute hepatocellular injury. However, at the same time point, pretreatment with xanthohumol almost completely blunted the I/R-induced AKT and NFκB activation and the expression of the proinflammatory genes IL-1alpha, IL-6, MCP-1 and ICAM-1, which are known to play a crucial role in the subacute phase of I/R-induced liver damage. In conclusion, these data indicate the potential of xanthohumol application to prevent adverse inflammatory responses to I/R-induced liver damage such as after surgical liver resection or transplantation. [Copyright &y& Elsevier]

Abstract: Two new polyisoprenylated acylphloroglucinols, thoreliones A and B, and a new polyisoprenylated tetracyclic xanthone, oxy-thorelione A, together with twelve known compounds, were isolated from the bark of Calophyllum thorelii. The new structures were determined using spectroscopic methods and chemical modification. The major compound thorelione A (1) showed moderate cytotoxic activity against MCF-7, HeLa and NCI-H460 cells with IC50 values of 7.4, 9.3 and 10.6μg/mL, respectively, using the sulforhodamine B assay. [Copyright &y& Elsevier]

Abstract: Purified oligomers of hyalobiuronic acid are indispensable tools to elucidate the physiological and pathophysiological role of hyaluronan degradation by various hyaluronidase isoenzymes. Therefore, we established and validated a novel sensitive, convenient, rapid, and cost-effective high performance thin layer chromatography (HPTLC) method for the qualitative and quantitative analysis of small saturated hyaluronan oligosaccharides consisting of 2–4 hyalobiuronic acid moieties. The use of amino-modified silica as stationary phase allows a simple reagent-free in situ derivatization by heating, resulting in a very low limit of detection (7–19pmol per band, depending on the analyzed saturated oligosaccharide). By this derivatization procedure for the first time densitometric quantification of the analytes could be performed by HPTLC. The validated method showed a quantification limit of 37–71pmol per band and was proven to be superior in comparison to conventional detection of hyaluronan oligosaccharides. The analytes were identified by hyphenation of normal phase planar chromatography to mass spectrometry (TLC–MS) using electrospray ionization. As an alternative to sequential techniques such as high performance liquid chromatography (HPLC) and capillary electrophoresis (CE), the validated HPTLC quantification method can easily be automated and is applicable to the analysis of multiple samples in parallel. [Copyright &y& Elsevier]

Abstract: Five acylphloroglucinols substituted with monoterpenoids (empetrifelixin A–D and empetrikajaforin), three known monocyclic acylphloroglucinols and one monocyclic acylphloroglucinol were isolated from a petrol ether extract of Hypericum empetrifolium after fractionation by flash chromatography on silica gel, RP-18 and subsequent purification by preparative HPLC (RP-18). Their structures were elucidated by 1D, 2D NMR techniques and HREIMS. To determine a possible anti-angiogenic activity, inhibition of cell proliferation was measured using a human microvascular endothelial cell line (HMEC-1). Subconfluent grown HMEC-1 cells were treated with all compounds isolated in sufficient amounts and stained with crystal violet. Highest activity was observed for empetrifelixin A and empetrifelixin D showing a concentration dependent inhibition of cell proliferation with IC50 values of 6.5±0.1 and 7.3±0.4μM, respectively. Empetrifelixin A also showed activity in a cell migration assay with HMEC-1 cells in low micromolar concentrations. [Copyright &y& Elsevier]

Abstract: Female inflorescences of the hop plant Humulus lupulus L. contain a variety of secondary metabolites with bitter acids (BA) as quantitatively dominating secondary metabolites. The use of hops in beer brewing has a long history due to the antibacterial effects of the BA and their typical bitter taste. Furthermore, hop cones are used in traditional medicine and for pharmaceutical purposes. Recent studies indicate that BA may affect activity of the transcription factor NFκB. NFκB plays a key role in the activation process of hepatic stellate cells (HSC), which is the key event of hepatic fibrosis. The aim of this study was to investigate the effect of BA on HSC (activation) and their potential to inhibit molecular processes involved in the pathogenesis of hepatic fibrosis. HSC were isolated from murine and human liver tissue and incubated with a characterized fraction of bitter acids purified from a CO2 hop extract. At a concentration of 25μg/ml BA started to induce LDH leakage. Already at lower concentrations BA lead to a dose dependent inhibition of HSC proliferation and inhibited IκB-α-phosphorylation, nuclear p65 translocation and binding activity in a dose dependent way (up to 10μg/ml). Accordingly, the same BA-doses inhibited the expression of pro-inflammatory and NFκB regulated genes as MCP-1 and RANTES, but did not affect expression of genes not related to NFκB signaling. In addition to the effect on activated HSC, BA inhibited the in vitro activation process of freshly isolated HSC as evidenced by delayed expression of collagen I and α-SMA mRNA and protein. Together, these findings indicate that BA inhibit NFκB activation, and herewith the activation and development of profibrogenic phenotype of HSC. Thus, bitter acids appear as potential functional nutrients for the prevention or treatment hepatic fibrosis in chronic liver disease. [Copyright &y& Elsevier]

Abstract: Globospiramine (1), a new spirobisindole alkaloid possessing an Aspidosperma–Aspidosperma skeleton, together with deoxyvobtusine (2), deoxyvobtusine lactone (3), vobtusine lactone (4) and lupeol (5), were isolated and identified from Voacanga globosa through a bioassay-guided purification. The gross structure and absolute stereochemistry of 1 were established by circular dichroism spectroscopy, HR-MS and unambiguous NMR spectroscopic experiments. In addition, a new biogenetic pathway for the formation of the spiro-Aspidosperma-Aspidosperma skeleton is proposed. Alkaloid 1 showed potent antituberculosis activity against Mycobacterium tuberculosis H37Rv as evidenced in microplate Alamar blue assay (MIC = 4 μg/mL) and low-oxygen recovery assay (LORA (MIC = 5.2 μg/mL). The bisindole alkaloids also exhibited promising activity against acetylcholinesterase and, especially butyrylcholinesterase, with deoxyvobtusine (2) (IC50 = 6.2 μM) as the most strongly inhibiting compound. This study extends the variety of alkaloid structural platforms which exhibit antimycobacterial and anticholinesterase activity. [Copyright &y& Elsevier]

Mixed stands of Senecio ovatus subsp. ovatus and S. germanicus subsp. germanicus occur in the colline belt of central and eastern Europe. The latter species is adapted to more continental climate conditions and shows a later flowering time (August-September) than the widespread S. ovatus (July-August) that grows in more oceanic climates. We have surveyed 253 plants from 15 populations north of Regensburg (south-eastern Germany) using 16 qualitative and quantitative morphological characters and molecular markers [amplified fragment length polymorphisms (AFLP)] to detect introgressive hybridisation between these two species. Both multivariate statistical analyses based on morphological characters and the Bayesian clustering based on AFLP fingerprint data show that in most populations under study the two species form distinct entities and do not hybridise with each other. However, in one population from the Upper Palatine Forest a high number of intermediate individuals were found. A more detailed genetic (AFLP) and phytochemical (pyrrolizidine alkaloid, PA) analysis based on 125 individuals from this hybrid swarm indicated that these intermediate individuals are backcrosses towards S. germanicus. It is shown that the two species differ considerably concerning the qualitative and quantitative PA patterns and that backcrossed individuals either show an additive PA pattern or a PA pattern similar to S. germanicus, while in quantitative respects all of these individuals are approaching S. germanicus. These findings are discussed in terms of differential selection regimes influencing the fitness of pure and hybrid plants in an area which is an eco-climatological optimum for the more oceanic S. ovatus but which forms a distributional edge for the more continental S. germanicus. [ABSTRACT FROM AUTHOR]

The chemopreventive chalcone xanthohumol (Xh) has been reported to decrease xanthine oxidase (XOD) catalysed formation of formazan from nitroblue tetrazolium (NBT) and is discussed as a potent scavenger of superoxide. Re-evaluation of the scavenging capacity indicated that Xh disturbed detection of superoxide with NBT, in case of an insufficient NBT/Xh ratio. Xh lacked superoxide scavenging activity in contrast to the Xh-derivative 3′-hydroxy-Xh with catechol substructure, used as positive control. This was shown by the use of sufficient concentration of NBT and other detectors such as hydroxylamine, XTT, cytochrome c and hydroethidine. HPLC analysis of reaction products in a xanthine/XOD/peroxidase system demonstrated beside enhanced inhibition of NBT-formazan by Xh that NBT even prevented oxidation of Xh. p-coumaric acid or ferulic acid could replace Xh in that system, indicating that superoxide detection using NBT is likely jeopardized by interference of phenoxyl-radicals. Furthermore, this study provides evidence that Xh can moderately generate superoxide via auto-oxidation. [ABSTRACT FROM AUTHOR]

A pyrene-labeled Zn2+-cyclen complex for the staining of DNA in agarose gels is reported. The metal chelate coordinates reversibly to the DNA phosphate backbone, which induces the formation of pyrene excimers. The typical pyrene excimer emission is used for the detection of the DNA. Staining is limited to agarose gels and is less sensitive than ethidium bromide, but DNA amounts as low as 10 ng and short DNA strands (∼300 b.p.) are detectable. Gel extraction as a standard technique in molecular biology was successfully performed after staining with Zn2+-cyclen-pyrene. Cytotoxicity tests on HeLa and V-79 cells reveal that the zinc-cyclen pyrene probe is significant less toxic compared to ethidium bromide. [ABSTRACT FROM AUTHOR]

Abstract: Xanthohumol, the major prenylated chalcone found in hops, is known to exert several beneficial effects but only few studies evaluated the safety profile of this natural compound with in part discrepant results. Here, we fed female BALB/c mice with a standard diet supplemented with xanthohumol for 3weeks, and thus, achieved a daily dose of approximately 1000mg xanthohumol/kg body weight. There were no significant differences in body weight or food intake between mice on standard diet and animals receiving the same diet supplemented with xanthohumol. Histopathological examination of liver, kidney, colon, lung, heart, spleen and thymus revealed no signs of xanthohumol-toxicity, and biochemical serum analysis confirmed normal organ function. Further, xanthohumol treatment did not affect hepatic glycogen content CYP2E1 and CYP1A2 expression levels, but CYP3A11 mRNA was approximately 30% reduced. Expression of several genes indicative of early hepatic inflammation and fibrosis, a hallmark of chronic liver injury, did not differ between xanthohumol treated and control mice. In summary, these results indicate that oral administration of xanthohumol exhibits no adverse effects on major organ function and homoeostasis in mice. Particularly, hepatotoxic effects could be ruled out confirming a good safety profile of xanthohumol as prerequisite for further studies in humans. [Copyright &y& Elsevier]

Abstract: Besides 2′,4′-dihydroxy-4,6′-dimethoxy-3′-prenylchalcone (1) and 4-acetoxy-2′,4′-dihydroxy-6′-methoxy-3′-prenylchalkon (2), both phase II metabolites of xanthohumol in rats, also a principally new chalcone 3′-coumaroyl-2′,4,4′-trihydroxy-6′-methoxychalcone (3), structurally derived from helichrysetin (4) by introducing a second coumaroyl substructure at C-3′ was synthesized. Furthermore new chalcones were synthesized by combination of the B-Ring fragments of helichrysetin, xanthohumol, xanthohumol C and xanthohumol H with ferulic or caffeic acid moieties in Ring A. Compound 3 showed the highest cytotoxic activity against HeLa cells with an IC50 value of 7.3±0.4μM. Anti-oxidative effects were determined in the ORAC assay and revealed very strong activity for 3 and 3-methoxyhelichrysetin (6) exhibiting 7.7±0.3 and 6.0±1.3 Trolox equivalents, respectively. The anti-inflammatory activity of all compounds was measured in an in vitro ICAM-1 assay with human microvascular endothelial cells (HMEC-1) and compared with the activity of other structurally related chalcones. The results showed increasing anti-inflammatory activity for the new synthetic chalcones exhibiting a caffeoyl substructure with 3-hydroxyhelichrysetin (5) and 3-hydroxyxanthohumol H (14) being the most active. At 10μM the TNFα induced expression of ICAM-1 was significantly reduced to 65.8 and 69.6% of control, respectively. [Copyright &y& Elsevier]

Introgressive hybridisation between Senecio hercynicus and Senecio ovatus (Compositae, Senecioneae) was studied in a mixed stand of the two species on the S- and SW-facing slopes of the German part of the Bohemian Forest (SE Germany). Morphological variation based on multivariate analysis of 14 diagnostic characters, along with genetic data from an amplified fragment length polymorphism (AFLP) fingerprinting analysis, indicates that the surveyed stand forms an intensively introgressed hybrid swarm. The majority of individuals were found to be intermediate between the two parental taxa, and strong statistical correlation between phenetic and genetic distances was observed. In contrast to that, flowering time of individuals (expressed as the time when 50% of the capitula of a plant were in flower) was found to follow a bimodal distribution in the hybrid swarm and lacked any correlation with the genetic and morphological relationships among plants. The same was true for the spectra of pyrrolizidine alkaloids (PA) revealed by a gas-chromatographic survey: most of the 142 individuals surveyed fell into one of two main chemotypes, only a few plants exhibited an intermediate and additive PA spectrum, and no correlation with the genetic and morphological relationships among plants was observed. Assuming that most of the AFLP markers are neutral, we conclude that the correlation of morphology with the genetic pattern may argue for the neutrality of morphological features analysed. Consequently, we interpret the lack of correlation between phenological and phytochemical data with the neutral genetic markers as evidence that both phenology and phytochemistry may be either under selection or that these features are genetically or biosynthetically constrained. [ABSTRACT FROM AUTHOR]