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Leonova, T.; Popova, V.; Tsarev, A.; Henning, C.; Antonova, K.; Rogovskaya, N.; Vikhnina, M.; Baldensperger, T.; Soboleva, A.; Dinastia, E.; Dorn, M.; Shiroglasova, O.; Grishina, T.; Balcke, G. U.; Ihling, C.; Smolikova, G.; Medvedev, S.; Zhukov, V. A.; Babakov, V.; Tikhonovich, I. A.; Glomb, M. A.; Bilova, T.; Frolov, A. Does Protein Glycation Impact on the Drought-Related Changes in Metabolism and Nutritional Properties of Mature Pea (Pisum sativum L.) Seeds? Int J Mol Sci 21, 567, (2020) DOI: 10.3390/ijms21020567

Protein glycation is usually referred to as an array of non-enzymatic post-translational modifications formed by reducing sugars and carbonyl products of their degradation. The resulting advanced glycation end products (AGEs) represent a heterogeneous group of covalent adducts, known for their pro-inflammatory effects in mammals, and impacting on pathogenesis of metabolic diseases and ageing. In plants, AGEs are the markers of tissue ageing and response to environmental stressors, the most prominent of which is drought. Although water deficit enhances protein glycation in leaves, its effect on seed glycation profiles is still unknown. Moreover, the effect of drought on biological activities of seed protein in mammalian systems is still unstudied with respect to glycation. Therefore, here we address the effects of a short-term drought on the patterns of seed protein-bound AGEs and accompanying alterations in pro-inflammatory properties of seed protein in the context of seed metabolome dynamics. A short-term drought, simulated as polyethylene glycol-induced osmotic stress and applied at the stage of seed filling, resulted in the dramatic suppression of primary seed metabolism, although the secondary metabolome was minimally affected. This was accompanied with significant suppression of NF-kB activation in human SH-SY5Y neuroblastoma cells after a treatment with protein hydrolyzates, isolated from the mature seeds of drought-treated plants. This effect could not be attributed to formation of known AGEs. Most likely, the prospective anti-inflammatory effect of short-term drought is related to antioxidant effect of unknown secondary metabolite protein adducts, or down-regulation of unknown plant-specific AGEs due to suppression of energy metabolism during seed filling.

Tabassum, N.; Eschen‐Lippold, L.; Athmer, B.; Baruah, M.; Brode, M.; Maldonado‐Bonilla, L. D.; Hoehenwarter, W.; Hause, G.; Scheel, D.; Lee, J. Phosphorylation‐dependent control of an RNA granule‐localized protein that fine‐tunes defence gene expression at a post‐transcriptional level Plant J 101, 1023-1039, (2020) DOI: 10.1111/tpj.14573

Mitogen‐activated protein kinase (MAPK) cascades are key signalling modules of plant defence responses to pathogen‐associated molecular patterns (PAMPs, e.g. bacterial flg22 peptide). The Tandem Zinc Finger Protein 9 (TZF9) is an RNA‐binding protein that is phosphorylated by two PAMP‐responsive MAPKs, MPK3 and MPK6. We mapped the major phosphosites in TZF9 and showed their importance for controlling in vitro RNA‐binding activity, in vivo flg22‐induced rapid disappearance of TZF9‐labelled processing body‐like structures and TZF9 protein turnover. Microarray analysis showed a strong discordance between transcriptome (total mRNA) and translatome (polysome‐associated mRNA) in the tzf9 mutant, with more mRNAs associated to ribosomes in the absence of TZF9. This suggests that TZF9 may sequester and inhibit translation of subsets of mRNAs. Fittingly, TZF9 physically interacts with poly(A)‐binding protein 2 (PAB2), a hallmark constituent of stress granules – a site for stress‐induced translational stalling/arrest. TZF9 even promotes stress granule assembly in the absence of stress. Hence, MAPKs may control defence gene expression post‐transcriptionally through release from translation arrest within TZF9‐PAB2‐containing RNA granules or perturbing PAB2 functions in translation control (e.g. in the mRNA closed‐loop model of translation).
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da Silva, I. C. V.; de Oliveira, P. F.; Barbosa, G. M.; Wessjohann, L. A.; Cardozo-Filho, L.; Holandino, C.; Muzitano, M. F.; Leal, I. C. R. Passiflora mucronata leaves extracts obtained from different methodologies: a phytochemical study based on cytotoxic and apoptosis activities of triterpenes and phytosterols constituents Braz J Pharm Sci (2020) DOI: 10.1590/s2175-97902019000417666

Cancer is one of the most prevalent diseases worldwide and the natural products could be a source of bioactive compounds. Passiflora mucronata (PM) belongs to a very known vegetal genus, although, there are no studies about cytotoxic activity or isolated compounds. Different extracts from PM were obtained by liquid-liquid partition (P), Soxhlet (Sox) and supercritical fluid (SFE1-5) extraction techniques, being compared concerning their yields, chemical profile and cytotoxicity. The Sox extracts showed the highest yields (6.03%: hexane; 2.51%: dichloromethane) followed by SFE (from 4.34 to 1.63%) and partitions (1.06 and 2.26%). The hexane partition (HP) showed the best cytotoxic activity against K562 cell line (IC50 = 18.72 µg.mL-1). From HP, the following compounds were identified and analysed its cytotoxic activities: β-amyrin (IC50 = 3.92 µg.mL-1), β-sitosterol (IC50 = 3.37 µg.mL-1), stigmasterol (IC50 = 3.31 µg.mL-1) and oleanolic acid. Stigmasterol induced about 75% of K562 total apoptosis. The compounds were tested against MA-104 cell line and the selective index (SI) attributed (SI >10 for all compounds). This indicates good selectivity to K562 cell line at the expense of MA-104. This is the first time, identifying those compounds to PM .

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.

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.

Seixas, N.; Ravanello, B. B.; Morgan, I.; Kaluđerović, G. N.; Wessjohann, L. A. Chlorambucil Conjugated Ugi Dendrimers with PAMAM-NH2 Core and Evaluation of Their Anticancer Activity Pharmaceutics 11, 59, (2019) DOI: 10.3390/pharmaceutics11020059

Herein, a new Ugi multicomponent reaction strategy is described to enhance activity and solubility of the chemotherapeutic drug chlorambucil through its conjugation to poly(amidoamine) (PAMAM-NH2) dendrimers with the simultaneous introduction of lipidic (i-Pr) and cationic (–NH2) or anionic (–COOH) groups. Standard viability assays were used to evaluate the anticancer potential of the water-soluble dendrimers against PC-3 prostate and HT-29 colon cancer cell lines, as well as non-cancerous mouse NIH3T3 fibroblasts. It could be demonstrated that the anticancer activity against PC-3 cells was considerably improved when both chlorambucil and –NH2 (cationic) groups were present on the dendrimer surface (1b). Additionally, this dendrimer showed activity only against the prostate cancer cells (PC-3), while it did not affect colon cancer cells and fibroblasts significantly. The cationic chlorambucil-dendrimer 1b blocks PC-3 cells in the G2/M phase and induces caspase independent apoptosis.

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.
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Makong, Y. S.; Fotso, G. W.; Mouthe, G. H.; Lenta, B.; Rennert, R.; Sewald, N.; Arnold, N.; Wansi, J. D.; Ngadjui, B. T. Bruceadysentoside A, a new pregnane glycoside and others secondary metabolites with cytotoxic activity from brucea antidysenterica J. F. Mill. (simaroubaceae) Nat Prod Res (2019) DOI: 10.1080/14786419.2019.1655024

The chemical investigation of the root barks leaves and stem barks of Brucea antidysenterica J. F. Mill. (Simaroubaceae) led to the isolation of a new pregnane glycoside, named Bruceadysentoside A or 3-O-β-L-arabinopyranosyl-pregn-5-en-20-one (1) together with seventeen known compounds. Their structures were established from spectral data, mainly HRESIMS, 1 D and 2 D NMR and by comparison with literature data. Compounds 1, 2, 5, 6, 8, 10, 12 and 13 were tested in vitro for their effects on the viability of two different human cancer cell lines, namely prostate PC-3 adenocarcinoma cells and colorectal HT-29 adenocarcinoma cells. No substantial activities were recorded for 2, 10, 12 and 13 (up to 10 μM concentration). 1, 5 and 8 did not show strong anti-proliferative effects up to 100 μM, however, 6 exhibited a stronger anti-proliferative effect with IC50 values of ∼ 100 μM against PC-3 and ∼ 200 μM against HT-29.

Sakna, S. T.; Mocan, A.; Sultani, H. N.; El-fiky, N. M.; Wessjohann, L. A.; Farag, M. A. Metabolites profiling of Ziziphus leaf taxa via UHPLC/PDA/ESI-MS in relation to their biological activities Food Chem 293, 233-246, (2019) DOI: 10.1016/j.foodchem.2019.04.097

Ziziphus plants are well recognized for their nutritive and medicinal value worldwide, albeit their chemical profile has yet to be fully reported. The secondary metabolites profile of three traditionally used Ziziphus leaf accessions was investigated via ultra-high performance liquid chromatography coupled to photodiode array and electrospray ionization mass detectors (UHPLC/PDA/ESI-MS). A total of 102 metabolites were characterized revealing the first holistic approach onto Ziziphus leaf metabolome and to include the first report of several novel flavonoids and cyclopeptide alkaloids. Fragmentation pattern for cyclopeptide alkaloids was proposed via ESI-MS. Principal component analysis (PCA) revealed close metabolite resemblance among Z. spina-christi and Z. mauritiana leaf specimens found enriched in saponins and distinct from that of Z. jujuba in which quercetin-3-O-(2-pentosyl)-rhamnoside was most abundant. Further, in-vitro antioxidant, anti-inflammatory and antidiabetic assays revealed for Z. spina-christi and Z. mauritiana strong effects compared to Z. jujuba and in correlation with their metabolites repertoire.

Pantelić, N. Đ.; 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.

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