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Publikation

Fröhlich, C.; Zschiebsch, K.; Gröger, V.; Paarmann, K.; Steffen, J.; Thurm, C.; Schropp, E.-M.; Brüning, T.; Gellerich, F.; Radloff, M.; Schwabe, R.; Lachmann, I.; Krohn, M.; Ibrahim, S.; Pahnke, J.; Activation of Mitochondrial Complex II-Dependent Respiration Is Beneficial for α-Synucleinopathies Mol. Neurobiol. 53, 4728-4744, (2016) DOI: 10.1007/s12035-015-9399-4

Parkinson’s disease and dementia with Lewy bodies are major challenges in research and clinical medicine world-wide and contribute to the most common neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to enhance clearance of amyloid-β from the brain of APP-transgenic mice leading to beneficial clinical outcome. It has been discussed whether specific mitochondrial alterations contribute to disease progression or even prevent toxic peptide deposition, as seen in many neurodegenerative diseases. Here, we investigated α-synuclein-transgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNAArg genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new model has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α-synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegeneration. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and oligomers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α-synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.
Publikation

Edeler, D.; Kaluđerović, M. R.; Dojčinović, B.; Schmidt, H.; Kaluđerović, G. N.; SBA-15 mesoporous silica particles loaded with cisplatin induce senescence in B16F10 cells RSC Adv. 6, 111031-111040, (2016) DOI: 10.1039/C6RA22596A

The anticancer drug cisplatin (CP) is loaded into SBA-15 mesoporous silica (SBA-15|CP) and its release from the nanomaterial is studied. The CP-loaded SBA-15 is tested against four tumor cell lines: mouse malignant melanoma B16F10, human adenocarcinoma HeLa, colon HT-29 and prostate PC3. Most importantly, the superiority of this novel material in comparison to CP arises from the fact that the CP-grafted nanomaterial SBA-15 (→SBA-15|CP) is enhancing cessation of proliferation along with induction of senescence in B16F10 in approximately 3.5 times lower concentration. The control material loaded with therapeutically inactive K2[PtCl4] (→SBA-15|TC) showed no antitumor activity. To a large extent, SBA-15|CP-induced senescence might present a safe approach in tumor treatment. Such cells can be cleared by immune cells resulting in efficient tumor regression. So far only apoptotic agents are being exploited in clinics, thus an understanding of the chemotherapeutic-induced senescence will allow oncologists to explore this essential tumor suppressor mechanism.
Publikation

Bilova, T.; Lukasheva, E.; Brauch, D.; Greifenhagen, U.; Paudel, G.; Tarakhovskaya, E.; Frolova, N.; Mittasch, J.; Balcke, G. U.; Tissier, A.; Osmolovskaya, N.; Vogt, T.; Wessjohann, L. A.; Birkemeyer, C.; Milkowski, C.; Frolov, A.; A Snapshot of the Plant Glycated Proteome: STRUCTURAL, FUNCTIONAL, AND MECHANISTIC ASPECTS J. Biol. Chem. 291, 7621-7636, (2016) DOI: 10.1074/jbc.M115.678581

Glycation is the reaction of carbonyl compounds (reducing sugars and α-dicarbonyls) with amino acids, lipids, and proteins, yielding early and advanced glycation end products (AGEs). The AGEs can be formed via degradation of early glycation intermediates (glycoxidation) and by interaction with the products of monosaccharide autoxidation (autoxidative glycosylation). Although formation of these potentially deleterious compounds is well characterized in animal systems and thermally treated foods, only a little information about advanced glycation in plants is available. Thus, the knowledge of the plant AGE patterns and the underlying pathways of their formation are completely missing. To fill this gap, we describe the AGE-modified proteome of Brassica napus and characterize individual sites of advanced glycation by the methods of liquid chromatography-based bottom-up proteomics. The modification patterns were complex but reproducible: 789 AGE-modified peptides in 772 proteins were detected in two independent experiments. In contrast, only 168 polypeptides contained early glycated lysines, which did not resemble the sites of advanced glycation. Similar observations were made with Arabidopsis thaliana. The absence of the early glycated precursors of the AGE-modified protein residues indicated autoxidative glycosylation, but not glycoxidation, as the major pathway of AGE formation. To prove this assumption and to identify the potential modifying agents, we estimated the reactivity and glycative potential of plant-derived sugars using a model peptide approach and liquid chromatography-mass spectrometry-based techniques. Evaluation of these data sets together with the assessed tissue carbohydrate contents revealed dihydroxyacetone phosphate, glyceraldehyde 3-phosphate, ribulose, erythrose, and sucrose as potential precursors of plant AGEs.
Publikation

Bernstein, H.-G.; Hildebrandt, J.; Dobrowolny, H.; Steiner, J.; Bogerts, B.; Pahnke, J.; Morphometric analysis of the cerebral expression of ATP-binding cassette transporter protein ABCB1 in chronic schizophrenia: Circumscribed deficits in the habenula Schizophr. Res. 177, 52-58, (2016) DOI: 10.1016/j.schres.2016.02.036

There is increasing evidence that microvascular abnormalities and malfunction of the blood–brain barrier (BBB) significantly contribute to schizophrenia pathophysiology. The ATP-binding cassette transporter ABCB1 is an important molecular component of the intact BBB, which has been implicated in a number of neurodegenerative and psychiatric disorders, including schizophrenia. However, the regional and cellular expression of ABCB1 in schizophrenia is yet unexplored. Therefore, we studied ABCB1 protein expression immunohistochemically in twelve human post-mortem brain regions known to play a role in schizophrenia, in 13 patients with schizophrenia and nine controls. In ten out of twelve brain regions under study, no significant differences were found with regard to the numerical density of ABCB1-expressing capillaries between all patients with schizophrenia and control cases. The left and right habenular complex, however, showed significantly reduced capillary densities in schizophrenia patients. In addition, we found a significantly reduced density of ABCB1-expressing neurons in the left habenula. Reduced ABCB1 expression in habenular capillaries might contribute to increased brain levels of proinflammatory cytokines in patients with schizophrenia, while decreased expression of this protein in a subpopulation of medial habenular neurons (which are probably purinergic) might be related to abnormalities of purines and their receptors found in this disease.
Publikation

Bensing, C.; Mojić, M.; Gómez-Ruiz, S.; Carralero, S.; Dojčinović, B.; Maksimović-Ivanić, D.; Mijatović, S.; Kaluđerović, G. N.; Evaluation of functionalized mesoporous silica SBA-15 as a carrier system for Ph3Sn(CH2)3OH against the A2780 ovarian carcinoma cell line Dalton Trans. 45, 18984-18993, (2016) DOI: 10.1039/C6DT03519A

SBA-15|Sn3, a mesoporous silica-based material (derivative of SBA-15) loaded with an organotin compound Ph3Sn(CH2)3OH (Sn3), possesses improved antitumor potential against the A2780 high-grade serous ovarian carcinoma cell line in comparison to Sn3. It is demonstrated that both the compound and the nanostructured material are internalized by the A2780 cells. A similar mode of action of Sn3 and SBA-15|Sn3 against the A2780 cell line was found. Explicitly, induction of apoptosis, caspase 2, 3, 8 and 9 activation, accumulation of cells in the hypodiploid phase as well as accumulation of ROS were observed. Interestingly, Sn3 loaded in the mesoporous silica-based material needed to reach a concentration 3.5 times lower than the IC50 value of the Sn3 compound, pointing out a higher effect of the SBA-15|Sn3 than Sn3 alone. Clonogenic potential, growth in 3D culture as well as mobility of cells were disturbed in the presence of SBA-15|Sn3. Such behavior could be associated with the suppression of p-38 MAPK. Less profound effect of Sn3 compared to SBA-15|Sn3 could be attributed to a different regulation of p-38 and STAT-3, which are mainly responsible for an appropriate cellular response to diverse stimuli or metastatic properties.
Publikation

Alresly, Z.; Lindequist, U.; Lalk, M.; Porzel, A.; Arnold, N.; Wessjohann, L. A.; Bioactive Triterpenes from the Fungus Piptoporus betulinus Rec. Nat. Prod. 10, 103-108, (2016)

Phytochemical investigation of the ethyl acetate extract of the fruiting bodies from the basidiomycete Piptoporus betulinus led to the isolation of a new bioactive lanostane triterpene identified as 3 b -acetoxy-16-hydroxy-24-oxo-5α-lanosta-8- ene-21-oic acid (1). In addition, ten known triterpenes, polyporenic acid A (5), polyporenic acid C (4), three derivatives of polyporenic acid A (8, 10, 11), betulinic acid (3), betulin (2), ergosterol peroxide (6), 9,11-dehydroergosterol peroxide (7), and fomefficinic acid (9), were also isolated from the fungus. All isolated compounds were tested for antimicrobial activity against some Gram-positive and Gram-negative bacteria as well as against a fungal strain. The new triterpene and some of the other compounds showed antimicrobial activity against Gram-positive bacteria.
Publikation

Steffen, J.; Krohn, M.; Paarmann, K.; Schwitlick, C.; Brüning, T.; Marreiros, R.; Müller-Schiffmann, A.; Korth, C.; Braun, K.; Pahnke, J.; Revisiting rodent models: Octodon degus as Alzheimer’s disease model? Acta Neuropathol. Commun. 4, 91, (2016) DOI: 10.1186/s40478-016-0363-y

Alzheimer’s disease primarily occurs as sporadic disease and is accompanied with vast socio-economic problems. The mandatory basic research relies on robust and reliable disease models to overcome increasing incidence and emerging social challenges. Rodent models are most efficient, versatile, and predominantly used in research. However, only highly artificial and mostly genetically modified models are available. As these ‘engineered’ models reproduce only isolated features, researchers demand more suitable models of sporadic neurodegenerative diseases. One very promising animal model was the South American rodent Octodon degus, which was repeatedly described as natural ‘sporadic Alzheimer’s disease model’ with ‘Alzheimer’s disease-like neuropathology’. To unveil advantages over the ‘artificial’ mouse models, we re-evaluated the age-dependent, neurohistological changes in young and aged Octodon degus (1 to 5-years-old) bred in a wild-type colony in Germany. In our hands, extensive neuropathological analyses of young and aged animals revealed normal age-related cortical changes without obvious signs for extensive degeneration as seen in patients with dementia. Neither significant neuronal loss nor enhanced microglial activation were observed in aged animals. Silver impregnation methods, conventional, and immunohistological stains as well as biochemical fractionations revealed neither amyloid accumulation nor tangle formation. Phosphoepitope-specific antibodies against tau species displayed similar intraneuronal reactivity in both, young and aged Octodon degus.In contrast to previous results, our study suggests that Octodon degus born and bred in captivity do not inevitably develop cortical amyloidosis, tangle formation or neuronal loss as seen in Alzheimer’s disease patients or transgenic disease models.
Publikation

Shaaban, S.; Negm, A.; Ashmawy, A. M.; Ahmed, D. M.; Wessjohann, L. A.; Combinatorial synthesis, in silico, molecular and biochemical studies of tetrazole-derived organic selenides with increased selectivity against hepatocellular carcinoma Eur. J. Med. Chem. 122, 55-71, (2016) DOI: 10.1016/j.ejmech.2016.06.005

Novel tetrazole-based diselenides and selenoquinones were synthesized via azido-Ugi and sequential nucleophilic substitution (SN) strategy. Molecular docking study into mammalian TrxR1 was used to predict the anticancer potential of the newly synthesized compounds. The cytotoxic activity of the compounds was evaluated using hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cancer cells and compared with their cytotoxicity in normal fibroblast (WI-38) cells. The corresponding redox properties of the synthesized compounds were assessed employing 2,2-diphenyl-1-picrylhydrazyl (DPPH), glutathione peroxidase (GPx)-like activity and bleomycin dependent DNA damage. In general, diselenides showed preferential cytotoxicity to HepG2 compared to MCF-7 cells. These compounds exhibited also good GPx catalytic activity compared to ebselen (up to 5 fold). Selenoquinones 18, 21, 22 and 23 were selected to monitor the expression levels of caspase-8, Bcl-2 and Ki-67 molecular biomarkers. Interestingly, these compounds downregulated the Bcl-2 and Ki-67 expression levels and activated the expression of caspase-8 in HepG2 cells compared to untreated cells. These results indicate that some of the newly synthesized compounds possess anti-HepG2 activity.
Publikation

Paudel, G.; Bilova, T.; Schmidt, R.; Greifenhagen, U.; Berger, R.; Tarakhovskaya, E.; Stöckhardt, S.; Balcke, G. U.; Humbeck, K.; Brandt, W.; Sinz, A.; Vogt, T.; Birkemeyer, C.; Wessjohann, L.; Frolov, A.; Osmotic stress is accompanied by protein glycation in Arabidopsis thaliana J. Exp. Bot. 67, 6283-6295, (2016) DOI: 10.1093/jxb/erw395

Among the environmental alterations accompanying oncoming climate changes, drought is the most important factor influencing crop plant productivity. In plants, water deficit ultimately results in the development of oxidative stress and accumulation of osmolytes (e.g. amino acids and carbohydrates) in all tissues. Up-regulation of sugar biosynthesis in parallel to the increasing overproduction of reactive oxygen species (ROS) might enhance protein glycation, i.e. interaction of carbonyl compounds, reducing sugars and α-dicarbonyls with lysyl and arginyl side-chains yielding early (Amadori and Heyns compounds) and advanced glycation end-products (AGEs). Although the constitutive plant protein glycation patterns were characterized recently, the effects of environmental stress on AGE formation are unknown so far. To fill this gap, we present here a comprehensive in-depth study of the changes in Arabidopsis thaliana advanced glycated proteome related to osmotic stress. A 3 d application of osmotic stress revealed 31 stress-specifically and 12 differentially AGE-modified proteins, representing altogether 56 advanced glycation sites. Based on proteomic and metabolomic results, in combination with biochemical, enzymatic and gene expression analysis, we propose monosaccharide autoxidation as the main stress-related glycation mechanism, and glyoxal as the major glycation agent in plants subjected to drought.
Publikation

Pantelić, N.; Stanković, D. M.; Zmejkovski, B. B.; Kaluđerović, G. N.; Sabo, T. J.; Electrochemical properties of some gold(III) complexes with (S,S)-R2edda-type ligands Int. J. Electrochem. Sci. 11, 1162-1171, (2016)

Oxidation-reduction properties of eleven gold(III) complexes with (S,S)-R2edda-type ligands was studied by cyclic and differential pulse voltammetry in DMSO. Series I: [AuCl2{(S,S)-R2eddip}]PF6, (S,S)-eddip = (S,S)-ethylenediamine-N,N’-di-2-propanoate, R = n-butyl, n-pentyl, isobutyl, isoamyl, cyclopentyl, 1–5; II: [AuCl2{(S,S)-R2eddch}]PF6, (S,S)-eddch = (S,S)-ethylenediamine-N,N’-di-2-(3-cyclohexyl)propanoate, R = methyl, ethyl, n-propyl, n-butyl, isobutyl, isoamyl, 6–11. Voltammograms in DMSO showed two successive irreversible reduction steps, where AuI species were the final reduction product. Reduction potential values are in range from 116 to 156 mV (Ep1) and –520 to –572 mV (Ep2) for Series I and from 148 to 228 mV (Ep1) and –569 to –638 mV (Ep2) for Series II. In general, slightly easier reduction of complexes belonging to Series I (higher cytotoxicity) could be due to less steric hindrance around the gold center. Reduction potentials and anticancer activity are not in correlation.

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