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Publikation

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.
Publikation

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.
Publikation

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.
Publikation

Lam, Y. T. H.; Palfner, G.; Lima, C.; Porzel, A.; Brandt, W.; Frolov, A.; Sultani, H.; Franke, K.; Wagner, C.; Merzweiler, K.; Wessjohann, L. A.; Arnold, N.; Nor-guanacastepene pigments from the Chilean mushroom Cortinarius pyromyxa Phytochemistry 165, 112048, (2019) DOI: 10.1016/j.phytochem.2019.05.021

For the first time, the pigment composition of basidiocarps from the Chilean mushroom Cortinarius pyromyxa was studied under various aspects like phylogeny, chemistry and antibiotic activity. A molecular biological study supports the monotypic position of C. pyromyxa in subgenus Myxacium, genus Cortinarius. Four undescribed diterpenoids, named pyromyxones A-D, were isolated from fruiting bodies of C. pyromyxa. Their chemical structures were elucidated based on comprehensive one- and two-dimensional NMR spectroscopic analysis, ESI-HRMS measurements, as well as X-ray crystallography. In addition, the absolute configurations of pyromyxones A-D were established with the aid of JH,H, NOESY spectra and quantum chemical CD calculation. The pyromyxones A-D possess the undescribed nor-guanacastane skeleton. Tested pyromyxones A, B, and D exhibit only weak activity against gram-positive Bacillus subtilis and gram-negative Aliivibrio fischeri as well as the phytopathogenic fungi Botrytis cinerea, Septoria tritici and Phytophthora infestans.
Publikation

Kufka, R.; Rennert, R.; Kaluđerović, G. N.; Weber, L.; Richter, W.; Wessjohann, L. A.; Synthesis of a tubugi-1-toxin conjugate by a modulizable disulfide linker system with a neuropeptide Y analogue showing selectivity for hY1R-overexpressing tumor cells Beilstein J. Org. Chem. 15, 96-105, (2019) DOI: 10.3762/bjoc.15.11

Tubugi-1 is a small cytotoxic peptide with picomolar cytotoxicity. To improve its cancer cell targeting, it was conjugated using a universal, modular disulfide derivative. This allowed conjugation to a neuropeptide-Y (NPY)-inspired peptide [K4(C-βA-),F7,L17,P34]-hNPY, acting as NPY Y1 receptor (hY1R)-targeting peptide, to form a tubugi-1–SS–NPY disulfide-linked conjugate. The cytotoxic impacts of the novel tubugi-1–NPY peptide–toxin conjugate, as well as of free tubugi-1, and tubugi-1 bearing the thiol spacer (liberated from tubugi-1–NPY conjugate), and native tubulysin A as reference were investigated by in vitro cell viability and proliferation screenings. The tumor cell lines HT-29, Colo320 (both colon cancer), PC-3 (prostate cancer), and in conjunction with RT-qPCR analyses of the hY1R expression, the cell lines SK-N-MC (Ewing`s sarcoma), MDA-MB-468, MDA-MB-231 (both breast cancer) and 184B5 (normal breast; chemically transformed) were investigated. As hoped, the toxicity of tubugi-1 was masked, with IC50 values decreased by ca. 1,000-fold compared to the free toxin. Due to intracellular linker cleavage, the cytotoxic potency of the liberated tubugi-1 that, however, still bears the thiol spacer (tubugi-1-SH) was restored and up to 10-fold higher compared to the entire peptide–toxin conjugate. The conjugate shows toxic selectivity to tumor cell lines overexpressing the hY1R receptor subtype like, e.g., the hard to treat triple-negative breast cancer MDA-MB-468 cells.
Publikation

Krohn, M.; Zoufal, V.; Mairinger, S.; Wanek, T.; Paarmann, K.; Brüning, T.; Eiriz, I.; Brackhan, M.; Langer, O.; Pahnke, J.; Generation and Characterization of an Abcc1 Humanized Mouse Model (hABCC1flx/flx) with Knockout Capability Mol. Pharmacol. 96, 138-147, (2019) DOI: 10.1124/mol.119.115824

ATP-binding cassette (ABC) transporters such as ABCB1 (P-glycoprotein), ABCC1 (MRP1), and ABCG2 (BCRP) are well known for their role in rendering cancer cells resistant to chemotherapy. Additionally, recent research provided evidence that, along with other ABC transporters (ABCA1 and ABCA7), they might be cornerstones to tackle neurodegenerative diseases. Overcoming chemoresistance in cancer, understanding drug-drug interactions, and developing efficient and specific drugs that alter ABC transporter function are hindered by a lack of in vivo research models, which are fully predictive for humans. Hence, the humanization of ABC transporters in mice has become a major focus in pharmaceutical and neurodegenerative research. Here, we present a characterization of the first Abcc1 humanized mouse line. To preserve endogenous expression profiles, we chose to generate a knockin mouse model that leads to the expression of a chimeric protein that is fully human except for one amino acid. We found robust mRNA and protein expression within all major organs analyzed (brain, lung, spleen, and kidney). Furthermore, we demonstrate the functionality of the expressed human ABCC1 protein in brain and lungs using functional positron emission tomography imaging in vivo. Through the introduction of loxP sites, we additionally enabled this humanized mouse model for highly sophisticated studies involving cell type–specific transporter ablation. Based on our data, the presented mouse model appears to be a promising tool for the investigation of cell-specific ABCC1 function. It can provide a new basis for better translation of preclinical research.
Publikation

Krajnović, T.; Drača, D.; Kaluđerović, G. N.; Dunđerović, D.; Mirkov, I.; Wessjohann, L. A.; Maksimović-Ivanić, D.; Mijatović, S.; The hop-derived prenylflavonoid isoxanthohumol inhibits the formation of lung metastasis in B16-F10 murine melanoma model Food Chem. Toxicol. 129, 257-268, (2019) DOI: 10.1016/j.fct.2019.04.046

Isoxanthohumol (IXN), a prenylflavonoid from hops and beer, gained increasing attention as a potential chemopreventive agent. In the present study, IXN antimetastatic potential in vitro against the highly invasive melanoma cell line B16-F10 and in vivo in a murine metastatic model was investigated. Melanoma cell viability was diminished in a dose-dependent manner following the treatment with IXN. This decrease was a consequence of autophagy and caspase-dependent apoptosis. Additionally, the dividing potential of highly proliferative melanoma cells was dramatically affected by this isoflavanone, which was in correlation with an abrogated cell colony forming potential, indicating changes in their metastatic features. Concordantly, IXN promoted strong suppression of the processes that define metastasis– cell adhesion, invasion, and migration. Further investigation at the molecular level revealed that the abolished metastatic potential of a melanoma subclone was due to disrupted integrin signaling. Importantly, these results were reaffirmed in vivo where IXN inhibited the development of lung metastatic foci in tumor-challenged animals. The results of the present study may highlight the beneficial effects of IXN on melanoma as the most aggressive type of skin cancer and will hopefully shed a light on the possible use of this prenylflavonoid in the treatment of metastatic malignancies.
Publikation

Soboleva, A.; Mavropulo-Stolyarenko, G.; Karonova, T.; Thieme, D.; Hoehenwarter, W.; Ihling, C.; Stefanov, V.; Grishina, T.; Frolov, A.; Multiple Glycation Sites in Blood Plasma Proteins as an Integrated Biomarker of Type 2 Diabetes Mellitus Int. J. Mol. Sci. 20, 2329, (2019) DOI: 10.3390/ijms20092329

Type 2 diabetes mellitus (T2DM) is one of the most widely spread metabolic diseases. Because of its asymptomatic onset and slow development, early diagnosis and adequate glycaemic control are the prerequisites for successful T2DM therapy. In this context, individual amino acid residues might be sensitive indicators of alterations in blood glycation levels. Moreover, due to a large variation in the half-life times of plasma proteins, a generalized biomarker, based on multiple glycation sites, might provide comprehensive control of the glycemic status across any desired time span. Therefore, here, we address the patterns of glycation sites in highly-abundant blood plasma proteins of T2DM patients and corresponding age- and gender-matched controls by comprehensive liquid chromatography-mass spectrometry (LC-MS). The analysis revealed 42 lysyl residues, significantly upregulated under hyperglycemic conditions. Thereby, for 32 glycation sites, biomarker behavior was demonstrated here for the first time. The differentially glycated lysines represented nine plasma proteins with half-lives from 2 to 21 days, giving access to an integrated biomarker based on multiple protein-specific Amadori peptides. The validation of this biomarker relied on linear discriminant analysis (LDA) with random sub-sampling of the training set and leave-one-out cross-validation (LOOCV), which resulted in an accuracy, specificity, and sensitivity of 92%, 100%, and 85%, respectively.
Publikation

Shumilina, J.; Kusnetsova, A.; Tsarev, A.; Janse van Rensburg, H. C.; Medvedev, S.; Demidchik, V.; Van den Ende, W.; Frolov, A.; Glycation of Plant Proteins: Regulatory Roles and Interplay with Sugar Signalling? Int. J. Mol. Sci. 20, 2366, (2019) DOI: 10.3390/ijms20092366

Glycation can be defined as an array of non-enzymatic post-translational modifications of proteins formed by their interaction with reducing carbohydrates and carbonyl products of their degradation. Initial steps of this process rely on reducing sugars and result in the formation of early glycation products—Amadori and Heyns compounds via Schiff base intermediates, whereas their oxidative degradation or reactions of proteins with α-dicarbonyl compounds yield a heterogeneous group of advanced glycation end products (AGEs). These compounds accompany thermal processing of protein-containing foods and are known to impact on ageing, pathogenesis of diabetes mellitus and Alzheimer’s disease in mammals. Surprisingly, despite high tissue carbohydrate contents, glycation of plant proteins was addressed only recently and its physiological role in plants is still not understood. Therefore, here we summarize and critically discuss the first steps done in the field of plant protein glycation during the last decade. We consider the main features of plant glycated proteome and discuss them in the context of characteristic metabolic background. Further, we address the possible role of protein glycation in plants and consider its probable contribution to protein degradation, methylglyoxal and sugar signalling, as well as interplay with antioxidant defense.
Publikation

Shaaban, S.; Ashmawy, A. M.; Negm, A.; Wessjohann, L. A.; Synthesis and biochemical studies of novel organic selenides with increased selectivity for hepatocellular carcinoma and breast adenocarcinoma Eur. J. Med. Chem. 179, 515-526, (2019) DOI: 10.1016/j.ejmech.2019.06.075

Nineteen organoselenides were synthesized and tested for their intrinsic cytotoxicity in hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines and their corresponding selective cytotoxicity (SI) was estimated using normal lung fibroblast (WI-38) cells. Most of the organic selenides exhibited good anticancer activity, and this was more pronounced in HepG2 cells. Interestingly, the naphthoquinone- (5), thiazol- (12), and the azo-based (13) organic selenides demonstrated promising SI (up to 76). Furthermore, the amine 4c, naphthoquinone 5, and azo-based 13 and 15 organic selenides were able to down-regulate the expression of Bcl-2 and up-regulate the expression levels of IL-2, IL-6 and CD40 in HepG2 cells compared to untreated cells. Moreover, most of the synthesized candidates manifested good free radical-scavenging and GPx-like activities comparable to vitamin C and ebselen. The obtained results suggested that some of the presented organoselenium candidates have promising anti-HepG2 and antioxidant activities.

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