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Displaying results 1 to 10 of 26.

Publications

Feilcke, R.; Arnouk, G.; Raphane, B.; Richard, K.; Tietjen, I.; Andrae-Marobela, K.; Erdmann, F.; Schipper, S.; Becker, K.; Arnold, N.; Frolov, A.; Reiling, N.; Imming, P.; Fobofou, S. A. T.; Biological activity and stability analyses of knipholone anthrone, a phenyl anthraquinone derivative isolated from Kniphofia foliosa Hochst. J. Pharm. Biomed. Anal. 174, 277-285, (2019) DOI: 10.1016/j.jpba.2019.05.065

Knipholone (1) and knipholone anthrone (2), isolated from the Ethiopian medicinal plant Kniphofia foliosa Hochst. are two phenyl anthraquinone derivatives, a compound class known for biological activity. In the present study, we describe the activity of both 1 and 2 in several biological assays including cytotoxicity against four human cell lines (Jurkat, HEK293, SH-SY5Y and HT-29), antiplasmodial activity against Plasmodium falciparum 3D7 strain, anthelmintic activity against the model organism Caenorhabditis elegans, antibacterial activity against Aliivibrio fischeri and Mycobacterium tuberculosis and anti-HIV-1 activity in peripheral blood mononuclear cells (PBMCs) infected with HIV-1c. In parallel, we investigated the stability of knipholone (2) in solution and in culture media. Compound 1 displays strong cytotoxicity against Jurkat, HEK293 and SH-SY5Y cells with growth inhibition ranging from approximately 62–95% when added to cells at 50 μM, whereas KA (2) exhibits weak to strong activity with 26, 48 and 70% inhibition of cell growth, respectively. Both 1 and 2 possess significant antiplasmodial activity against Plasmodium falciparum 3D7 strain with IC50 values of 1.9 and 0.7 μM, respectively. These results complement previously reported data on the cytotoxicity and antiplasmodial activity of 1 and 2. Furthermore, compound 2 showed HIV-1c replication inhibition (growth inhibition higher than 60% at tested concentrations 0.5, 5, 15 and 50 μg/ml and an EC50 value of 4.3 μM) associated with cytotoxicity against uninfected PBMCs. The stability study based on preincubation, HPLC and APCI-MS (atmospheric-pressure chemical ionization mass spectrometry) analysis indicates that compound 2 is unstable in culture media and readily oxidizes to form compound 1. Therefore, the biological activity attributed to 2 might be influenced by its degradation products in media including 1 and other possible dimers. Hence, bioactivity results previously reported from this compound should be taken with caution and checked if they differ from those of its degradation products. To the best of our knowledge, this is the first report on the anti-HIV activity and stability analysis of compound 2.
Publications

Farag, M. A.; El-Kersh, D. M.; Ehrlich, A.; Choucry, M. A.; El-Seedi, H.; Frolov, A.; Wessjohann, L. A.; Variation in Ceratonia siliqua pod metabolome in context of its different geographical origin, ripening stage and roasting process Food Chem. 283, 675-687, (2019) DOI: 10.1016/j.foodchem.2018.12.118

Carob is a legume tree of a considerable commercial importance for the flavor and sweet industry. In this context, it is cultivated mostly for its pods, which are known for their nutritive value and multiple health benefits. However, metabolite patterns, underlying these properties are still mostly uncharacterized. In this study, the role of geographical origin, ontogenetic changes and thermal processing on the Ceratonia siliqua pod metabolome was assessed by mass spectrometry (MS)-based metabolomics. Thereby, a total of 70 fruits primary metabolites, represented mainly by carbohydrates, organic and amino acids were detected. Analysis of secondary bioactive metabolites assessed by ultra-high-performance liquid chromatography-electrospray ionization high resolution mass spectrometry (UHPLC-ESI-HR-MS) revealed in total 83 signals. The major signals, most significantly contributing in discrimination of C. siliqua specimens were assigned to tannins and flavonoids. PCA models derived from either UHPLC-MS or GC-MS proved to be powerful tools for discrimination of C. siliqua specimens.
Publications

Drača, D.; Mijatović, S.; Krajnović, T.; Pristov, J. B.; Đukić, T.; Kaluđerović, G. N.; Wessjohann, L. A.; Maksimović-Ivanić, D.; The synthetic tubulysin derivative, tubugi-1, improves the innate immune response by macrophage polarization in addition to its direct cytotoxic effects in a murine melanoma model Exp. Cell Res. 380, 159-170, (2019) DOI: 10.1016/j.yexcr.2019.04.028

Synthetic tubugis are equally potent but more stable than their natural forms. Their anticancer potential was estimated on a solid melanoma in vitro and in vivo. Tubugi-1 induced the apoptosis in B16 cells accompanied with strong intracellular production of reactive species, subsequently imposing glutathione and thiol group depletion. Paradoxically, membrane lipids were excluded from the cascade of intracellular oxidation, according to malondialdehyde decrease. Although morphologically apoptosis was typical, externalization of phosphatidylserine (PS) as an early apoptotic event was not detected. Even their exposition is pivotal for apoptotic cell eradication, primary macrophages successfully eliminated PS-deficient tubugi-1 induced apoptotic cells. The tumor volume in animals exposed to the drug in therapeutic mode was reduced in comparison to control as well as to paclitaxel-treated animals. Importantly, macrophages isolated from tubugi-1 treated animals possessed conserved phagocytic activity and were functionally and phenotypically recognized as M1. The cytotoxic effect of tubugi-1 is accomplished through its ability to polarize the macrophages toward M1, probably by PS independent apoptotic cell engulfment. The unique potential of tubugi-1 to prime the innate immune response through the induction of a specific pattern of tumor cell apoptosis can be of extraordinary importance from fundamental and applicable aspects.
Publications

Drača, D.; Mijatović, S.; Krajnović, T.; Kaluđerović, G. N.; Wessjohann, L. A.; Maksimović-Ivanić, D.; Synthetic Tubulysin Derivative, Tubugi-1, Against Invasive Melanoma Cells: The Cell Death Triangle Anticancer Res. 39, 5403-5415, (2019) DOI: 10.21873/anticanres.13734

Background/Aim: Tubugi-1 is a more stable and accessible synthetic counterpart of natural tubulysins. This study aimed to evaluate its cytotoxic potential against anaplastic human melanoma cells. Materials and Methods: The viability of A-375 cells was determined by 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and crystal violet assay. The type of cell death and proliferative rate were investigated using flow cytometry and fluorescent microscopy, while the molecular background was evaluated by western blot. Results: Tubugi-1 reduced the viability of A-375 cells, inducing massive micronucleation, followed by augmented expression of inhibitor of nuclear factor-κB and caspase-2, typical of a mitotic catastrophe. Disturbed proliferation and G2M block with prominent caspase activity, weakened the expression of B-cell lymphoma 2 and B-cell lymphoma 2-associated X transient up-regulation, coexisted with intensive autophagy. Specific inhibition of autophagy by chloroquine resulted in conversion from mitotic catastrophe to rapid apoptosis. Conclusion: Multilevel anticancer action of tubugi-1 is extended by co-application of an autophagy inhibitor, giving a new dimension in further preclinical advancement of this potential agent.
Publications

Chantseva, V.; Bilova, T.; Smolikova, G.; Frolov, A.; Medvedev, S.; 3D-clinorotation induces specific alterations in metabolite profiles of germinating Brassica napus L. seeds Biol. Commun. 64, 55-74, (2019) DOI: 10.21638/spbu03.2019.107

During the whole history of their life on Earth, higher plants evolved under the constant gravity stimulus. Therefore, plants developed efficient mechanisms of gravity perception, underlying their ability to adjust the direction of growth to the gravity vector, i.e. the phenomenon of gravitropism. In this context, alterations in the magnitude and vector of the gravity field might compromise plant growth and development. This aspect was successfully addressed in gravity fields of low intensity (microgravity). On the other hand, microgravity can be simulated on the Earth by clinorotation, i.e. rotation of the experimental plant along one or several axes. This approach is routinely used for studies of gravity-related responses of crop plants, although the effect of simulated microgravity on the most sensitive ontogenetic stages — germination and seedling development — is still not sufficiently characterized. Recently, we addressed the effects of clinorotation on the proteome of germinating oilseed rape (Brassica napus) seeds. Here we extend this study to the seedling primary metabolome and address its changes in the presence of 3D-clinorotation. GC-MS analysis revealed essential alterations in patterns of sugars and sugar phosphates (specifically glucose-6-phosphate), methionine and glycerol. Thereby, abundances of individual metabolites showed high dispersion, indicating high lability and plasticity of the seedling metabolome.
Publications

Ceafalan, L. C.; Fertig, T. E.; Gheorghe, T. C.; Hinescu, M. E.; Popescu, B. O.; Pahnke, J.; Gherghiceanu, M.; Age-related ultrastructural changes of the basement membrane in the mouse blood-brain barrier J. Cell. Mol. Med. 23, 819-827, (2019) DOI: 10.1111/jcmm.13980

The blood‐brain barrier (BBB) is essential for a functional neurovascular unit. Most studies focused on the cells forming the BBB, but very few studied the basement membrane (BM) of brain capillaries in ageing. We used transmission electron microscopy and electron tomography to investigate the BM of the BBB in ageing C57BL/6J mice. The thickness of the BM of the BBB from 24‐month‐old mice was double as compared with that of 6‐month‐old mice (107 nm vs 56 nm). The aged BBB showed lipid droplets gathering within the BM which further increased its thickness (up to 572 nm) and altered its structure. The lipids appeared to accumulate toward the glial side of the BM. Electron tomography showed that the lipid‐rich BM regions are located in small pockets formed by the end‐feet of astrocytes. These findings suggest an imbalance of the lipid metabolism and that may precede the structural alteration of the BM. These alterations may favour the accretion of abnormal proteins that lead to neurodegeneration in ageing. These findings warrant further investigation of the BM of brain capillaries and of adjoining cells as potential targets for future therapies.
Publications

Podolskaya, E. P.; Gladchuk, A. S.; Keltsieva, O. A.; Dubakova, P. S.; Silyavka, E. S.; Lukasheva, E.; Zhukov, V.; Lapina, N.; Makhmadalieva, M. R.; Gzgzyan, A. M.; Sukhodolov, N. G.; Krasnov, K. A.; Selyutin, A. A.; Frolov, A.; Thin Film Chemical Deposition Techniques as a Tool for Fingerprinting of Free Fatty Acids by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry Anal. Chem. 91, 1636-1643, (2019) DOI: 10.1021/acs.analchem.8b05296

Metabolic fingerprinting is a powerful analytical technique, giving access to high-throughput identification and relative quantification of multiple metabolites. Because of short analysis times, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) is the preferred instrumental platform for fingerprinting, although its power in analysis of free fatty acids (FFAs) is limited. However, these metabolites are the biomarkers of human pathologies and indicators of food quality. Hence, a high-throughput method for their fingerprinting is required. Therefore, here we propose a MALDI-TOF-MS method for identification and relative quantification of FFAs in biological samples of different origins. Our approach relies on formation of monomolecular Langmuir films (LFs) at the interphase of aqueous barium acetate solution, supplemented with low amounts of 2,5-dihydroxybenzoic acid, and hexane extracts of biological samples. This resulted in detection limits of 10–13–10–14 mol and overall method linear dynamic range of at least 4 orders of magnitude with accuracy and precision within 2 and 17%, respectively. The method precision was verified with eight sample series of different taxonomies, which indicates a universal applicability of our approach. Thereby, 31 and 22 FFA signals were annotated by exact mass and identified by tandem MS, respectively. Among 20 FFAs identified in Fucus algae, 14 could be confirmed by gas chromatography-mass spectrometry.
Publications

Pantelić, N. ?.; Lerbs, M.; Wolf, K.; Wessjohann, L. A.; Kaluđerović, G. N.; In vitro anticancer evaluation of novel triphenyltin(IV) compounds with some N-acetyl-S-(naphthoquinone)cysteine derivatives J. Serb. Chem. Soc. 84, 1119-1127, (2019) DOI: 10.2298/JSC190322032P

Triphenyltin(IV) compounds with naphthoquinone derivatives containing N-acetylcysteine, N-acetyl-S-(1,2-dion-4-naphthyl)cysteine (1,2-NQC), 1, and N-acetyl-S-(1,4-dion-2-naphthyl)cysteine (1,4-NQC), 2, were synthesized and characterized by elemental microanalysis, IR, multinuclear (1H, 13C, 119Sn) NMR spectroscopy as well as HR-ESI mass spectrometry. With the aim of in vitro anticancer activity determination of ligand precursors and novel synthesized organotin(IV) compounds against human cervix adenocarcinoma (HeLa), human colon carcinoma (HT-29), and melanoma carcinoma cell line (B16F10), MTT colorimetric assay method was applied. The results indicate that synthesized compounds exhibited remarkable antiproliferative activity toward all tested cell lines with IC50 in the range of 0.17 to 0.87 μM. Complex 1 showed the greatest activity against HT-29 cells, with IC50 value of 0.21 ± 0.01 μM, 119 times better than cisplatin, while complex 2 demonstrated the highest activity toward HeLa cells, IC50 = 0.17 ± 0.01 μM, which is ~26 times better than cisplatin.
Publications

Paarmann, K.; Prakash, S. R.; Krohn, M.; Möhle, L.; Brackhan, M.; Brüning, T.; Eiriz, I.; Pahnke, J.; French maritime pine bark treatment decelerates plaque development and improves spatial memory in Alzheimer's disease mice Phytomedicine 57, 39-48, (2019) DOI: 10.1016/j.phymed.2018.11.033

BackgroundPlant extracts are increasingly investigated as potential drugs against Alzheimer's disease (AD) and dementia in general. Pycnogenol is an extract from the bark of the French maritime pine (Pinus pinaster Aiton subsp. atlantica) with known anti-oxidative and neuroprotective effects.Hypothesis/PurposePycnogenol is thought to improve cognitive functions in elderly. We wanted to investigate and quantify these effects in a model system of cerebral ß-amyloidosis/AD.Study design/methodsThis study experimentally assessed the effects of Pycnogenol on AD-related pathology in a ß-amyloidosis mouse model. APP-transgenic mice and controls were treated orally in a pre-onset and post-onset treatment paradigm. The effects of Pycnogenol were characterized by analysing ß-amyloid (Aß) plaques, number of neurons, glia coverage, myelination pattern, and cortical coverage with axons using immunohistochemistry. Aß levels were quantified using ELISA and gene expression levels of APP-processing enzymes ADAM10, BACE1 and IDE protein levels were determined by Western blot. Behavioural changes in circadian rhythm were monitored and spatial memory / cognition was assessed using a water maze test.ResultsPycnogenol significantly decreased the number of plaques in both treatment paradigms but did not alter levels of soluble Aß or the gene expression of APP-processing enzymes. The morphological analyses revealed no changes in the number of neurons, astrocytes, microglia, the myelination pattern, or the morphology of axons. Behavioural testing revealed an improvement of the spatial memory in the pre-onset treatment paradigm only.ConclusionOur results suggest to evaluate clinically a potential use of Pycnogenol in the prevention or in early stages of mild cognitive impairment (MCI) and AD.
Publications

Mamontova, T.; Afonin, A. M.; Ihling, C.; Soboleva, A.; Lukasheva, E.; Sulima, A. S.; Shtark, O. Y.; Akhtemova, G. A.; Povydysh, M. N.; Sinz, A.; Frolov, A.; Zhukov, V. A.; Tikhonovich, I. A.; Profiling of Seed Proteome in Pea (Pisum sativum L.) Lines Characterized with High and Low Responsivity to Combined Inoculation with Nodule Bacteria and Arbuscular Mycorrhizal Fungi Molecules 24, 1603, (2019) DOI: 10.3390/molecules24081603

Legume crops represent the major source of food protein and contribute to human nutrition and animal feeding. An essential improvement of their productivity can be achieved by symbiosis with beneficial soil microorganisms—rhizobia (Rh) and arbuscular mycorrhizal (AM) fungi. The efficiency of these interactions depends on plant genotype. Recently, we have shown that, after simultaneous inoculation with Rh and AM, the productivity gain of pea (Pisum sativum L) line K-8274, characterized by high efficiency of interaction with soil microorganisms (EIBSM), was higher in comparison to a low-EIBSM line K-3358. However, the molecular mechanisms behind this effect are still uncharacterized. Therefore, here, we address the alterations in pea seed proteome, underlying the symbiosis-related productivity gain, and identify 111 differentially expressed proteins in the two lines. The high-EIBSM line K-8274 responded to inoculation by prolongation of seed maturation, manifested by up-regulation of proteins involved in cellular respiration, protein biosynthesis, and down-regulation of late-embryogenesis abundant (LEA) proteins. In contrast, the low-EIBSM line K-3358 demonstrated lower levels of the proteins, related to cell metabolism. Thus, we propose that the EIBSM trait is linked to prolongation of seed filling that needs to be taken into account in pulse crop breeding programs. The raw data have been deposited to the ProteomeXchange with identifier PXD013479.

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