TY - JOUR A1 - Witt, Barbara A1 - Meyer, Sören A1 - Ebert, Franziska A1 - Francesconi, Kevin A. A1 - Schwerdtle, Tanja T1 - Toxicity of two classes of arsenolipids and their water-soluble metabolites in human differentiated neurons JF - Archives of toxicology : official journal of EUROTOX N2 - Arsenolipids are lipid-soluble organoarsenic compounds, mainly occurring in marine organisms, with arsenic-containing hydrocarbons (AsHCs) and arsenic-containing fatty acids (AsFAs) representing two major subgroups. Recently, toxicity studies of several arsenolipids showed a high cytotoxic potential of those arsenolipids in human liver and bladder cells. Furthermore, feeding studies with Drosophila melanogaster indicated an accumulation of arsenolipids in the fruit fly’s brain. In this study, the neurotoxic potential of three AsHCs, two AsFAs and three metabolites (dimethylarsinic acid, thio/oxo-dimethylarsenopropanoic acid) was investigated in comparison to the toxic reference arsenite (iAsIII) in fully differentiated human brain cells (LUHMES cells). Thereby, in the case of AsHCs both the cell number and cell viability were reduced in a low micromolar concentration range comparable to iAsIII, while AsFAs and the applied metabolites were less toxic. Mechanistic studies revealed that AsHCs reduced the mitochondrial membrane potential, whereas neither iAsIII nor AsFAs had an impact. Furthermore, neurotoxic mechanisms were investigated by examining the neuronal network. Here, AsHCs massively disturbed the neuronal network and induced apoptotic effects, while iAsIII and AsFAs showed comparatively lesser effects. Taking into account the substantial in vitro neurotoxic potential of the AsHCs and the fact that they could transfer across the physiological barriers of the brain, a neurotoxic potential in vivo for the AsHCs cannot be excluded and needs to be urgently characterized. KW - Arsenolipids KW - Neurons KW - Cytotoxicity KW - Neurotoxicity KW - Arsenic-containing hydrocarbons KW - Arsenic-containing fatty acids Y1 - 2017 U6 - https://doi.org/10.1007/s00204-017-1933-x SN - 0340-5761 SN - 1432-0738 VL - 91 SP - 3121 EP - 3134 PB - Springer CY - Heidelberg ER - TY - JOUR A1 - Lohren, Hanna A1 - Blagojevic, Lara A1 - Fitkau, Romy A1 - Ebert, Franziska A1 - Schildknecht, Stefan A1 - Leist, Marcel A1 - Schwerdtle, Tanja T1 - Toxicity of organic and inorganic mercury species in human neurons and human astrocytes JF - Journal of trace elements in medicine and biology N2 - Organic mercury (Hg) species exert their toxicity primarily in the central nervous system. The food relevant Hg species methylmercury (MeHg) has been frequently studied regarding its neurotoxic effects in vitro and in vivo. Neurotoxicity of thiomersal, which is used as a preservative in medical preparations, is to date less characterised. Due to dealkylation of organic Hg or oxidation of elemental Hg, inorganic Hg is present in the brain albeit these species are not able to readily cross the blood brain barrier. This study compared for the first time toxic effects of organic MeHg chloride (MeHgCl) and thiomersal as well as inorganic mercury chloride (HgCl2) in differentiated human neurons (LUHMES) and human astrocytes (CCF-STTG1). The three Hg species differ in their degree and mechanism of toxicity in those two types of brain cells. Generally, neurons are more susceptible to Hg species induced cytotoxicity as compared to astrocytes. This might be due to the massive cellular mercury uptake in the differentiated neurons. The organic compounds exerted stronger cytotoxic effects as compared to inorganic HgCl2. In contrast to HgCl2 exposure, organic Hg compounds seem to induce the apoptotic cascade in neurons following low-level exposure. No indicators for apoptosis were identified for both inorganic and organic mercury species in astrocytes. Our studies clearly demonstrate species-specific toxic mechanisms. A mixed exposure towards all Hg species in the brain can be assumed. Thus, prospectively coexposure studies as well as cocultures of neurons and astrocytes could provide additional information in the investigation of Hg induced neurotoxicity. KW - Methylmercury KW - Thiomersal KW - Mercuric mercury KW - Human differentiated neurons KW - Cytotoxicity KW - Apoptosis Y1 - 2015 U6 - https://doi.org/10.1016/j.jtemb.2015.06.008 SN - 0946-672X VL - 32 SP - 200 EP - 208 PB - Elsevier CY - Jena ER - TY - JOUR A1 - Marco, Makungu A1 - Deyou, Tsegaye A1 - Gruhonjic, Amra A1 - Holleran, John A1 - Duffy, Sandra A1 - Heydenreich, Matthias A1 - Firtzpatrick, Paul A. A1 - Landberg, Goran A1 - Koch, Andreas A1 - Derese, Solomon A1 - Pelletier, Jerry A1 - Avery, Vicky M. A1 - Erdelyi, Mate A1 - Yenesew, Abiy T1 - Pterocarpans and isoflavones from the root bark of Millettia micans and of Millettia dura JF - Phytochemistry letters KW - Millettia micans KW - Millettia dura KW - Pterocarpan KW - Isoflavone KW - Cytotoxicity KW - Plasmodium falciparum Y1 - 2017 U6 - https://doi.org/10.1016/j.phytol.2017.07.012 SN - 1874-3900 SN - 1876-7486 VL - 21 SP - 216 EP - 220 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Adem, Fozia A. A1 - Kuete, Victor A1 - Mbaveng, Armelle T. A1 - Heydenreich, Matthias A1 - Ndakala, Albert A1 - Irungu, Beatrice A1 - Efferth, Thomas A1 - Yenesew, Abiy T1 - Cytotoxic benzylbenzofuran derivatives from Dorstenia kameruniana JF - Fitoterapia N2 - Chromatographic separation of the extract of the roots of Dorstenia kameruniana (family Moraceae) led to the isolation of three new benzylbenzofuran derivatives, 2-(p-hydroxybenzyl)benzofuran-6-ol (1), 2-(p-hydroxybenzyl)-7-methoxybenzofuran-6-ol (2) and 2-(p-hydroxy)-3-(3-methylbut-2-en-1-yl)benzyl)benzofuran-6-ol (3) (named dorsmerunin A, B and C, respectively), along with the known furanocoumarin, bergapten (4). The twigs of Dorstenia kameruniana also produced compounds 1-4 as well as the known chalcone licoagrochalcone A (5). The structures were elucidated by NMR spectroscopy and mass spectrometry. The isolated compounds displayed cytotoxicity against the sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells, where compounds 4 and 5 had the highest activities (IC50 values of 7.17 mu M and 5.16 mu M, respectively) against CCRF-CEM leukemia cells. Compound 5 also showed cytotoxicity against 7 sensitive or drug-resistant solid tumor cell lines (breast carcinoma, colon carcinoma, glioblastoma), with IC50 below 50 mu M, whilst 4 showed selective activity. KW - Dorstenia kameruniana KW - Moraceae KW - Benzylbenzofuran KW - Furanocoumarin KW - Chalcone KW - Cytotoxicity Y1 - 2018 U6 - https://doi.org/10.1016/j.fitote.2018.04.019 SN - 0367-326X SN - 1873-6971 VL - 128 SP - 26 EP - 30 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Irungu, Beatrice N. A1 - Adipo, Nicholas A1 - Orwa, Jennifer A. A1 - Kimani, Francis A1 - Heydenreich, Matthias A1 - Midiwo, Jacob O. A1 - Bjoremark, Per Martin A1 - Hakansson, Mikael A1 - Yenesew, Abiy A1 - Erdelyi, Mate T1 - Antiplasmodial and cytotoxic activities of the constituents of Turraea robusta and Turraea nilotica JF - Journal of ethnopharmacology : an interdisciplinary journal devoted to bioscientific research on indigenous drugs N2 - Ethnopharmacological relevance: Turraea robusta and Turraea nilotica are African medicinal plants used for the treatment of a wide variety of diseases, including malaria. The genus Turraea is rich in limonoids and other triterpenoids known to possess various biological activities. Materials and methods: From the stem bark of T. robusta six compounds, and from various parts of T nilotica eleven compounds were isolated by the use of a combination of chromatographic techniques. The structures of the isolated compounds were elucidated using NMR and MS, whilst the relative configuration of one of the isolated compounds, toonapubesin F, was established by X-ray crystallography. The antiplasmodial activities of the crude extracts and the isolated constituents against the D6 and W2 strains of Plasmodium falciparum were determined using the semiautomated micro dilution technique that measures the ability of the extracts to inhibit the incorporation of (G-H-3, where G is guanine) hypoxanthine into the malaria parasite. The cytotoxicity of the crude extracts and their isolated constituents was evaluated against the mammalian cell lines African monkey kidney (vero), mouse breast cancer (4T1) and human larynx carcinoma (HEp2). Results: The extracts showed good to moderate antiplasmodial activities, where the extract of the stem bark of T. robusta was also cytotoxic against the 4T1 and the HEp2 cells (IC50 < 10 mu g/ml). The compounds isolated from these extracts were characterized as limonoids, protolimonoids and phytosterol glucosides. These compounds showed good to moderate activities with the most active one being azadironolide, IC50 2.4 +/- 0.03 mu M and 1.1 +/- 0.01 mu M against the D6 and W2 strains of Plasmodium falciparum, respectively; all other compounds possessed IC50 14.4-40.5 mu M. None of the compounds showed significant cytotoxicity against vero cells, yet four of them were toxic against the 4T1 and HEp2 cancer cell lines with piscidinol A having IC50 8.0 +/- 0.03 and 8.4 +/- 0.01 mu M against the 4T1 and HEp2 cells, respectively. Diacetylation of piscidinol A resulted in reduced cytotoxicity. Conclusion: From the medicinal plants T. robusta and T. nilotica, twelve compounds were isolated and characterized; two of the isolated compounds, namely 11-epi-toonacilin and azadironolide showed good antiplasmodial activity with the highest selectivity indices. (C) 2015 The Authors. Published by Elsevier Ireland Ltd. KW - Turraea robusta KW - Turraea nilotica KW - Antiplasmodial activity KW - Cytotoxicity KW - Limonoid KW - Toonapubesins F KW - Toonacilin KW - Azadironolide Y1 - 2015 U6 - https://doi.org/10.1016/j.jep.2015.08.039 SN - 0378-8741 VL - 174 SP - 419 EP - 425 PB - Elsevier CY - Clare ER - TY - JOUR A1 - Yaouba, Souaibou A1 - Koch, Andreas A1 - Guantai, Eric M. A1 - Derese, Solomon A1 - Irungu, Beatrice A1 - Heydenreich, Matthias A1 - Yenesew, Abiy T1 - Alkenyl cyclohexanone derivatives from Lannea rivae and Lannea schweinfurthii JF - Phytochemistry letters / Phytochemical Society of Europe N2 - Phytochemical investigation of the CH2Cl2/MeOH (1:1) extract of the roots of Lannea rivae (Chiov) Sacleux (Anacardiaceae) led to the isolation of a new alkenyl cyclohexenone derivative: (4R,6S)-4,6-dihydroxy-6-((Z)-nonadec-14′-en-1-yl)cyclohex-2-en-1-one (1), and a new alkenyl cyclohexanol derivative: (2S*,4R*,5S*)-2,4,5-trihydroxy-2-((Z)-nonadec-14′-en-1-yl)cyclohexanone (2) along with four known compounds, namely epicatechin gallate, taraxerol, taraxerone and β-sitosterol; while the stem bark afforded two known compounds, daucosterol and lupeol. Similar investigation of the roots of Lannea schweinfurthii (Engl.) Engl. led to the isolation of four known compounds: 3-((E)-nonadec-16′-enyl)phenol, 1-((E)-heptadec-14′-enyl)cyclohex-4-ene-1,3-diol, catechin, and 1-((E)-pentadec-12′-enyl)cyclohex-4-ene-1,3-diol. The structures of the isolated compounds were determined by NMR spectroscopy and mass spectrometry. The absolute configuration of compound 1 was established by quantum chemical ECD calculations. In an antibacterial activity assay using the microbroth kinetic method, compound 1 showed moderate activity against Escherichia coli while compound 2 exhibited moderate activity against Staphylococcus aureus. Compound 1 also showed moderate activity against E. coli using the disc diffusion method. The roots extract of L. rivae was notably cytotoxic against both the DU-145 prostate cancer cell line and the Vero mammalian cell line (CC50 = 5.24 and 5.20 μg/mL, respectively). Compound 1 was also strongly cytotoxic against the DU-145 cell line (CC50 = 0.55 μg/mL) but showed no observable cytotoxicity (CC50 > 100 μg/mL) against the Vero cell line. The roots extract of L. rivae and L. schweinfurthii, epicatechin gallate as well as compound 1 exhibited inhibition of carageenan-induced inflammation. KW - Lannea rivae KW - Lannea schweinfurthii KW - Alkenyl cyclohexenone KW - Alkenyl cyclohexanone KW - Anti-inflammatory KW - Cytotoxicity KW - Antimicrobial Y1 - 2017 U6 - https://doi.org/10.1016/j.phytol.2017.12.001 SN - 1874-3900 SN - 1876-7486 VL - 23 SP - 141 EP - 148 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Abdissa, Negera A1 - Heydenreich, Matthias A1 - Midiwo, Jacob O. A1 - Ndakala, Albert A1 - Majer, Zsuzsanna A1 - Neumann, Beate A1 - Stammler, Hans-Georg A1 - Sewald, Norbert A1 - Yenesew, Abiy T1 - A xanthone and a phenylanthraquinone from the roots of Bulbine frutescens, and the revision of six seco-anthraquinones into xanthones JF - Phytochemistry letters N2 - Phytochemical investigation of the dichloromethane/methanol (1:1) extract of the roots of Bulbine frutescens led to the isolation of a new xanthone, 8-hydroxy-6-methylxanthone-1-carboxylic acid (1) and a new phenylanthraquinone, 6',8-O-dimethylknipholone (2) along with six known compounds. The structures were elucidated on the basis of NMR and MS spectral data analyses. The structure of compound 1 was confirmed through X-ray crystallography which was then used as a reference to propose the revision of the structures of six seco-anthraquinones into xanthones. The isolated compounds were evaluated for cytotoxicity against human cervix carcinoma KB-3-1 cells with the phenylanthraquinone knipholone being the most active (IC50 = 0.43 mu M). Two semi-synthetic knipholone derivatives, knipholone Mannich base and knipholone-1,3-oxazine, were prepared and tested for cytotoxic activity; both showed moderate activities (IC50 value of 1.89 and 2.50 mu M, respectively). (C) 2014 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved. KW - Bulbine frutescens KW - Xanthone KW - seco-Anthraquinone KW - Phenylanthraquinone KW - Cytotoxicity KW - Structure revision Y1 - 2014 U6 - https://doi.org/10.1016/j.phytol.2014.04.004 SN - 1874-3900 SN - 1876-7486 VL - 9 SP - 67 EP - 73 PB - Elsevier CY - Amsterdam ER -