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Publikation

Smolikova, G.; Strygina, K.; Krylova, E.; Vikhorev, A.; Bilova, T.; Frolov, A.; Khlestkina, E.; Medvedev, S.; Seed-to-seedling transition in Pisum sativum L.: A transcriptomic approach Plants 11, 1686, (2022) DOI: 10.3390/plants11131686

The seed-to-seedling transition is a crucial step in the plant life cycle. The transition occurs at the end of seed germination and corresponds to the initiation of embryonic root growth. To improve our understanding of how a seed transforms into a seedling, we germinated the Pisum sativum L. seeds for 72 h and divided them into samples before and after radicle protrusion. Before radicle protrusion, seeds survived after drying and formed normally developed seedlings upon rehydration. Radicle protrusion increased the moisture content level in seed axes, and the accumulation of ROS first generated in the embryonic root and plumule. The water and oxidative status shift correlated with the desiccation tolerance loss. Then, we compared RNA sequencing-based transcriptomics in the embryonic axes isolated from pea seeds before and after radicle protrusion. We identified 24,184 differentially expressed genes during the transition to the post-germination stage. Among them, 2101 genes showed more prominent expression. They were related to primary and secondary metabolism, photosynthesis, biosynthesis of cell wall components, redox status, and responses to biotic stress. On the other hand, 415 genes showed significantly decreased expression, including the groups related to water deprivation (eight genes) and response to the ABA stimulus (fifteen genes). We assume that the water deprivation group, especially three genes also belonging to ABA stimulus (LTI65, LTP4, and HVA22E), may be crucial for the desiccation tolerance loss during a metabolic switch from seed to seedling. The latter is also accompanied by the suppression of ABA-related transcription factors ABI3, ABI4, and ABI5. Among them, HVA22E, ABI4, and ABI5 were highly conservative in functional domains and showed homologous sequences in different drought-tolerant species. These findings elaborate on the critical biochemical pathways and genes regulating seed-to-seedling transition.
Publikation

Predarska, I.; Saoud, M.; Drača, D.; Morgan, I.; Komazec, T.; Eichhorn, T.; Mihajlović, E.; Dunđerović, D.; Mijatović, S.; Maksimović-Ivanić, D.; Hey-Hawkins, E.; Kaluđerović, G. N.; Mesoporous silica nanoparticles enhance the anticancer efficacy of platinum(IV)-phenolate conjugates in breast cancer cell lines Nanomaterials 12, 3767, (2022) DOI: 10.3390/nano12213767

The main reasons for the limited clinical efficacy of the platinum(II)-based agent cisplatin include drug resistance and significant side effects. Due to their better stability, as well as the possibility to introduce biologically active ligands in their axial positions constructing multifunctional prodrugs, creating platinum(IV) complexes is a tempting strategy for addressing these limitations. Another strategy for developing chemotherapeutics with lower toxicity relies on the ability of nanoparticles to accumulate in greater quantities in tumor tissues through passive targeting. To combine the two approaches, three platinum(IV) conjugates based on a cisplatin scaffold containing in the axial positions derivatives of caffeic and ferulic acid were prepared and loaded into SBA-15 to produce the corresponding mesoporous silica nanoparticles (MSNs). The free platinum(IV) conjugates demonstrated higher or comparable activity with respect to cisplatin against different human breast cancer cell lines, while upon immobilization, superior antiproliferative activity with markedly increased cytotoxicity (more than 1000-fold lower IC50 values) compared to cisplatin was observed. Mechanistic investigations with the most potent conjugate, cisplatin-diacetyl caffeate (1), and the corresponding MSNs (SBA-15|1) in a 4T1 mouse breast cancer cell line showed that these compounds induce apoptotic cell death causing strong caspase activation. In vivo, in BALB/c mice, 1 and SBA-15|1 inhibited the tumor growth while decreasing the necrotic area and lowering the mitotic rate.
Publikation

Predarska, I.; Saoud, M.; Morgan, I.; Eichhorn, T.; Kaluđerović, G. N.; Hey-Hawkins, E.; Cisplatin−cyclooxygenase inhibitor conjugates, free and immobilised in mesoporous silica SBA-15, prove highly potent against triple-negative MDA-MB-468 breast cancer cell line Dalton Trans. 51, 857–869, (2022) DOI: 10.1039/d1dt03265h

For the development of anticancer drugs with higher activity and reduced toxicity, two approaches were combined: preparation of platinum(IV) complexes exhibiting higher stability compared to their platinum(II) counterparts and loading them into mesoporous silica SBA-15 with the aim to utilise the passive enhanced permeability and retention (EPR) effect of nanoparticles for accumulation in tumour tissues. Three conjugates based on a cisplatin scaffold bearing the anti-inflammatory drugs naproxen, ibuprofen or flurbiprofen in the axial positions (1, 2 and 3, respectively) were synthesised and loaded into SBA-15 to afford the mesoporous silica nanoparticles (MSNs) SBA-15|1, SBA-15|2 and SBA-15|3. Superior antiproliferative activity of both free and immobilised conjugates in a panel of four breast cancer cell lines (MDA-MB-468, HCC1937, MCF-7 and BT-474) with markedly increased cytotoxicity with respect to cisplatin was demonstrated. All compounds exhibit highest activity against the triple-negative cell line MDA-MB-468, with conjugate 1 being the most potent. However, against MCF-7 and BT-474 cell lines, the most notable improvement was found, with IC50 values up to 240-fold lower than cisplatin. Flow cytometry assays clearly show that all compounds induce apoptotic cell death elevating the levels of both early and late apoptotic cells. Furthermore, autophagy as well as formation of reactive oxygen species (ROS) and nitric oxide (NO) were elevated to a similar or greater extent than with cisplatin.
Publikation

Moura, P. H. B.; Brandt, W.; Porzel, A.; Martins, R. C. C.; Leal, I. C. R.; Wessjohann, L. A.; Structural elucidation of an atropisomeric entcassiflavan-(4β→8)-epicatechin isolated from Dalbergia monetaria L.f. based on NMR and ECD calculations in comparison to experimental data Molecules 27, 2512, (2022) DOI: 10.3390/molecules27082512

A rare dihydoxyflavan-epicatechin proanthocyanidin, entcassiflavan-(4β→8)-epicatechin, was isolated from Dalbergia monetaria, a plant widely used by traditional people from the Amazon to treat urinary tract infections. The constitution and relative configuration of the compound were elucidated by HR-MS and detailed 1D- and 2D-NMR measurements. By comparing the experimental electronic circular dichroism (ECD) spectrum with the calculated ECD spectra of all 16 possible isomers, the absolute configuration, the interflavan linkage, and the atropisomers could be determined.
Publikation

Bin Ware, I.; Franke, K.; Hussain, H.; Morgan, I.; Rennert, R.; Wessjohann, L. A.; Bioactive phenolic compounds from Peperomia obtusifolia Molecules 27, 4363, (2022) DOI: 10.3390/molecules27144363

Peperomia obtusifolia (L.) A. Dietr., native to Middle America, is an ornamental plant also traditionally used for its mild antimicrobial properties. Chemical investigation on the leaves of P. obtusifolia resulted in the isolation of two previously undescribed compounds, named peperomic ester (1) and peperoside (2), together with five known compounds, viz. N-[2-(3,4-dihydroxyphenyl)ethyl]-3,4-dihydroxybenzamide (3), becatamide (4), peperobtusin A (5), peperomin B (6), and arabinothalictoside (7). The structures of these compounds were elucidated by 1D and 2D NMR techniques and HREIMS analyses. Compounds 1–7 were evaluated for their anthelmintic (against Caenorhabditis elegans), antifungal (against Botrytis cinerea, Septoria tritici and Phytophthora infestans), antibacterial (against Bacillus subtilis and Aliivibrio fischeri), and antiproliferative (against PC-3 and HT-29 human cancer cell lines) activities. The known peperobtusin A (5) was the most active compound against the PC-3 cancer cell line with IC50 values of 25.6 µM and 36.0 µM in MTT and CV assays, respectively. This compound also induced 90% inhibition of bacterial growth of the Gram-positive B. subtilis at a concentration of 100 µM. In addition, compound 3 showed anti-oomycotic activity against P. infestans with an inhibition value of 56% by using a concentration of 125 µM. However, no anthelmintic activity was observed.
Publikation

Balarynová, J.; Klčová, B.; Sekaninová, J.; Kobrlová, L.; Cechová, M. Z.; Krejčí, P.; Leonova, T.; Gorbach, D.; Ihling, C.; Smržová, L.; Trněný, O.; Frolov, A.; Bednář, P.; Smýkal, P.; The loss of polyphenol oxidase function is associated with hilum pigmentation and has been selected during pea domestication New Phytol. 235, 1807–1821, (2022) DOI: 10.1111/nph.18256

Seed coats serve as protective tissue to the enclosed embryo. As well as mechanical there are also chemical defence functions. During domestication, the property of the seed coat was altered including the removal of the seed dormancy. We used a range of genetic, transcriptomic, proteomic and metabolomic approaches to determine the function of the pea seed polyphenol oxidase (PPO) gene. Sequencing analysis revealed one nucleotide insertion or deletion in the PPO gene, with the functional PPO allele found in all wild pea samples, while most cultivated peas have one of the three nonfunctional ppo alleles. PPO functionality cosegregates with hilum pigmentation. PPO gene and protein expression, as well as enzymatic activity, was downregulated in the seed coats of cultivated peas. The functionality of the PPO gene relates to the oxidation and polymerisation of gallocatechin in the seed coat. Additionally, imaging mass spectrometry supports the hypothesis that hilum pigmentation is conditioned by the presence of both phenolic precursors and sufficient PPO activity. Taken together these results indicate that the nonfunctional polyphenol oxidase gene has been selected during pea domestication, possibly due to better seed palatability or seed coat visual appearance.
Publikation

Vasco, A. V.; Ceballos, L. G.; Wessjohann, L. A.; Rivera, D. G.; Multicomponent functionalization of the octreotide peptide macrocyclic scaffold Eur. J. Org. Chem. 2022, e202200687, (2022) DOI: 10.1002/ejoc.202200687

The replacement of the disulfide bridge by other types of side chain linkages has been a continuous endeavor in the development of cyclic peptide drugs with improved metabolic stability. Octreotide is a potent and selective somatostatin analog that has been used as an anticancer agent, in radiolabeled conjugates for the localization of tumors and as targeting moiety in peptide-drug conjugates. Here, we describe an onresin methodology based on a multicomponent macrocyclization that enables the substitution of the disulfide bond by a tertiary lactam bridge functionalized with a variety of exocyclic moieties, including lipids, fluorophores, and charged groups. Conformational analysis in comparison with octreotide provides key information on the type of functionalization permitting the conformational mimicry of the bioactive peptide.
Publikation

Sultani, H. N.; Morgan, I.; Hussain, H.; Roos, A. H.; Haeri, H. H.; Kaluđerović, G. N.; Hinderberger, D.; Westermann, B.; Access to new cytotoxic triterpene and steroidal Acid-TEMPO Conjugates by ugi multicomponent-reactions Int. J. Mol. Sci. 22, 7125, (2021) DOI: 10.3390/ijms22137125

Multicomponent reactions, especially the Ugi-four component reaction (U-4CR), provide powerful protocols to efficiently access compounds having potent biological and pharmacological effects. Thus, a diverse library of betulinic acid (BA), fusidic acid (FA), cholic acid (CA) conjugates with TEMPO (nitroxide) have been prepared using this approach, which also makes them applicable in electron paramagnetic resonance (EPR) spectroscopy. Moreover, convertible amide modified spin-labelled fusidic acid derivatives were selected for post-Ugi modification utilizing a wide range of reaction conditions which kept the paramagnetic center intact. The nitroxide labelled betulinic acid analogue 6 possesses cytotoxic effects towards two investigated cell lines: prostate cancer PC3 (IC50 7.4 ± 0.7 μM) and colon cancer HT29 (IC50 9.0 ± 0.4 μM). Notably, spin-labelled fusidic acid derivative 8 acts strongly against these two cancer cell lines (PC3: IC50 6.0 ± 1.1 μM; HT29: IC50 7.4 ± 0.6 μM). Additionally, another fusidic acid analogue 9 was also found to be active towards HT29 with IC50 7.0 ± 0.3 μM (CV). Studies on the mode of action revealed that compound 8 increased the level of caspase-3 significantly which clearly indicates induction of apoptosis by activation of the caspase pathway. Furthermore, the exclusive mitochondria targeting of compound 18 was successfully achieved, since mitochondria are the major source of ROS generation.
Publikation

Smolikova, G.; Strygina, K.; Krylova, E.; Leonova, T.; Frolov, A.; Khlestkina, E.; Medvedev, S.; Transition from seeds to seedlings: Hormonal and epigenetic aspects Plants 10, 1884, (2021) DOI: 10.3390/plants10091884

Transition from seed to seedling is one of the critical developmental steps, dramatically affecting plant growth and viability. Before plants enter the vegetative phase of their ontogenesis, massive rearrangements of signaling pathways and switching of gene expression programs are required. This results in suppression of the genes controlling seed maturation and activation of those involved in regulation of vegetative growth. At the level of hormonal regulation, these events are controlled by the balance of abscisic acid and gibberellins, although ethylene, auxins, brassinosteroids, cytokinins, and jasmonates are also involved. The key players include the members of the LAFL network—the transcription factors LEAFY COTYLEDON1 and 2 (LEC 1 and 2), ABSCISIC ACID INSENSITIVE3 (ABI3), and FUSCA3 (FUS3), as well as DELAY OF GERMINATION1 (DOG1). They are the negative regulators of seed germination and need to be suppressed before seedling development can be initiated. This repressive signal is mediated by chromatin remodeling complexes—POLYCOMB REPRESSIVE COMPLEX 1 and 2 (PRC1 and PRC2), as well as PICKLE (PKL) and PICKLE-RELATED2 (PKR2) proteins. Finally, epigenetic methylation of cytosine residues in DNA, histone post-translational modifications, and post-transcriptional downregulation of seed maturation genes with miRNA are discussed. Here, we summarize recent updates in the study of hormonal and epigenetic switches involved in regulation of the transition from seed germination to the post-germination stage.
Publikation

Smolikova, G.; Leonova, T.; Vashurina, N.; Frolov, A.; Medvedev, S.; Desiccation tolerance as the basis of long-term seed viability Int. J. Mol. Sci. 22, 101, (2021) DOI: 10.3390/ijms22010101

Desiccation tolerance appeared as the key adaptation feature of photoautotrophic organisms for survival in terrestrial habitats. During the further evolution, vascular plants developed complex anatomy structures and molecular mechanisms to maintain the hydrated state of cell environment and sustain dehydration. However, the role of the genes encoding the mechanisms behind this adaptive feature of terrestrial plants changed with their evolution. Thus, in higher vascular plants it is restricted to protection of spores, seeds and pollen from dehydration, whereas the mature vegetative stages became sensitive to desiccation. During maturation, orthodox seeds lose up to 95% of water and successfully enter dormancy. This feature allows seeds maintaining their viability even under strongly fluctuating environmental conditions. The mechanisms behind the desiccation tolerance are activated at the late seed maturation stage and are associated with the accumulation of late embryogenesis abundant (LEA) proteins, small heat shock proteins (sHSP), non-reducing oligosaccharides, and antioxidants of different chemical nature. The main regulators of maturation and desiccation tolerance are abscisic acid and protein DOG1, which control the network of transcription factors, represented by LEC1, LEC2, FUS3, ABI3, ABI5, AGL67, PLATZ1, PLATZ2. This network is complemented by epigenetic regulation of gene expression via methylation of DNA, post-translational modifications of histones and chromatin remodeling. These fine regulatory mechanisms allow orthodox seeds maintaining desiccation tolerance during the whole period of germination up to the stage of radicle protrusion. This time point, in which seeds lose desiccation tolerance, is critical for the whole process of seed development.

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