Challenging drug target for Parkinson's disease: pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the elective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs. Therefore, the interactions of TPPP/p25 with tubulin and SYN were characterized which suggested the involvements of the 178–187 aa and 147–156 aa segments in the complexation of TPPP/p25 with tubulin and SYN, respectively. However, various truncated and deletion mutants reduced but did not abolish the interactions except one mutant; in addition synthetized fragments corresponding to the potential binding segments of TPPP/p25 failed to interact with SYN. In fact, the studies of the multiple interactions at molecular and cellular levels revealed the high conformational plasticity, chameleon feature, of TPPP/p25 that ensures exceptional functional resilience; the lack of previously identified binding segments could be replaced by other segments. The experimental results are underlined by distinct bioinformatics tools. All these data revealed that although targeting chameleon proteins is a challenging task, nevertheless, the validation of a drug target can be achieved by identifying the interface of complexes of the partner proteins existing at the given pathological conditions

Reviews

Reviews: 1. Láng Benedek: Klaniczay Gábor – Pócs Éva (eds.): Witchcraft and Demonology in Hungary and Transylvania : Palgrave Historical Studies in Witchcraft and Magic 2. Tamás Ildikó: Pócs Éva – Hesz Ágnes (eds.): Orvosistenektől a hortikulturális utópiáig. Tanulmányok a Kárpát-medence vonzáskörzetéből = From Gods of Medicine to Horticultural Utopias 3. Voigt Vilmos: Miskolczy Ambrus (ed.): Felvilágosodás és babonaság. Erdélyi néphiedelem-gyűjtés 1789-90-ben = Enlightenment and Superstitions. Collecting Folk Beliefs in Transylvania in 1789-1790 4. Kis-Halas Judit: Tóth G., Péter – Pakó László (eds.): Kolozsvári boszorkányperek 1564–1743 = Kolozsvár Witch Trials 1564–1743 és Tóth G., Péter – Brandl Gergely (eds.): Szegedi boszorkányperek 1726–1744 = Szeged Witch Trials 1726–1744 [összehasonlító ismertetés a két műről] 5. Tóth G. Péter: Bárth Dániel: A zombori ördögűző. Egy 18. századi ferences mentalitása = The Exorcist of Zombor: The Mentality of an Eighteenth-century Franciscan Friar 6. Vargyas Gábor: Balatonyi Judit: A gyimesi lakodalmak. Közös kultúra és különböző identitások? = Weddings in Gyimes. Common Culture, Dissimilar Identities

Generating Marker-Free Transgenic Wheat Using Minimal Gene Cassette and Cold-Inducible Cre/Lox System

The precise elimination of selectable marker genes is highly desirable, when their function is no longer needed, because their presence raised worldwide public concerns against the release of genetically modified plants. This is the first report of simultaneous application of the minimal gene cassette and cold-inducible Cre/lox recombination system in wheat. The bar selection and cre-recombinase genes were eliminated from T0 and T1 transgenic lines with 44 and 51 % efficiency. This approach provides a new, reasonably effective technique to produce selection gene-free transgenic wheat lines either immediately after tissue culture, or from the subsequent transgenic generation. The advantage of this method is that it does not require any additional cold treatment during the plant regeneration/growing because the transgene elimination is ensured by the vernalisation. Application of this method prevents gene flow by pollen and seed, because the selection and recombinase genes are eliminated before pollen development, therefore reducing the risk of GM plants. © 2014, Springer Science+Business Media New York

Hatékony tumorellenes készítmények előállítása target és drug molekulák kombinációjával = Synthesis of effective antitumoricidal compounds with the combination of target and drug molecules

Az irányított tumorterápiában alkalmazható új vegyületeket terveztünk és állítottunk elő. GnRH-III dimer származékok nagyobb tumorellenes hatást és kisebb endokrin aktivitást mutattak, mint a monomer. Enzim stabilitásuk szintén fokozódott. In vivo tumorellenes hatásukat HT-29 vastagbél tumort hordozó egereken tesztelve 50%-os gátlást értünk el. GnRH-I illetve GnRH-II és GnRH-III hormone peptideket tartalmazó vegyes dimereket is előállítottunk. T47-D emlőtumor sejteken 80% fölötti gátlást tapasztaltunk egy GnRH-I és GnRH-III peptidet tartalmazó dimer esetén. A dimerek szabadalmaztatása folyamatban van. A GnRH-III hormont hatóanyagok szállítására is felhasználtuk. Antraciklineket kapcsoltunk hozzá észter-, hidrazon- oxim és amidkötéssel. Az utobbi kivételével valamennyi konjugátum jelentős in vitro tumorellenes hatást mutatott. A daunorubicin-GnRH-III oximkötésű konjugátumot választottuk ki in vivo kísérletekhez C26 egér vastagbéltumort hordozó egereken. Ha a kezelést a 4. és 7. napon végeztük a tumorbeültetést követően, 40-50%-os tumornövekedés gátlást kaptunk (15 mg/kg Dau hatóanyag tartalom mellett). Ugyanakkor a konjugátum kivédte a drog toxikus hatását, és túlélésnövekedést is eredményezett a szabad droghoz képest. Ez az első olyan eredmény, ahol oximkötéssel konjugált daunorubicin származékkal tumorellenes hatást értek el. Tuftsin-szerű hordozómolekulák alkalmazásával kemotaxison alapuló hatóanyag célbajuttatást tudtunk megvalósítani. | New derivatives for targeted cancer therapy were developed. Dimers derived from GnRH-III had higher antitumor effect on cancer cells and lower activity on LH secretion than the monomer. Enhanced enzymatic stability of the dimers was also determined. The in vivo antitumor effect of the dimers was studied on HT-29 colon tumor bearing mice and 50% tumor growth inhibition was detected. Asymmetric dimer derivatives derived from GnRH-I or GnRH-II and GnRH-III were prepared. The combination of GnRH-I and GnRH-III resulted in a superagonist compound having 80% in vitro antiproliferative effect on T47-D human breast cancer cells. GnRH-III was also used as targeting moiety for anticancer drug delivery. Anthracyclines were attached to it via ester, hydrazone, oxime or amide bond. Except amide bond containing derivatives all compounds with other type of linkage have significant antitumor activity. Oxime bond-linked Daunorubicin?GnRH-III conjugate was selected for in vivo studies on C26 murine colon carcinoma bearing mice. The results showed that the application of the conjugate prevent the toxic side effect of the free drug. The highest tumor growth inhibition (40-50%) was observed when the treatments were performed on days 4 and 7 after tumor transplantation using 15 mg Dau content in conjugate/kg body weight. This is the first study indicating significant antitumor effect of a Dau-conjugate with oxime linkage. Chemotactic drug targeting with tuftsin like carriers was also used

Phenotypical and physiological study of near-isogenic durum wheat lines under contrasting water regimes

Irrigation treatments involving two water regimes were carried out in a controlled environment on eight nearisogenic durum wheat lines that differed in a major yield-related QTL region (QYld. idw-3B) in order to assess the relationship between morpho-physiological traits, antioxidant enzyme activities, and polyamine contents in the flag leaves, and drought tolerance. Drought stress, simulated under a rain-out shelter, negatively affected the performance of the isogenic lines, leading to significant reductions in seed yield, tiller number, chlorophyll content, plant height, leaf area, and ascorbate peroxidase activity, while the polyamine content and guaiacol peroxidase activity increased. The ascorbate peroxidase activity was negatively correlated with seed weight per main (r = -0.446) and side spike (r = -0.465) and the 1000-grain weight of the main and side spike (r = -0.396 and r = -0.49, respectively) and the guaiacol peroxidase activity with the number of seeds per main (r = -0.457) and side spike (r = -0.378) and the seed weight per side spike (r = -0.38). PUT, SPD, and SPN contents showed a significant positive relationship with the number of seeds per main spike (0.534***, 0.496***, and 0.481**, respectively) and the seed weight per main spike (0.383*, 0.352*, and 0.399**, respectively). ANOVA showed that the QYld. idw-3B++ lines had significantly better yield performance under non-watered conditions than the QYld. idw-3B--lines, but their response to drought stress was not uniform regarding other yield-related traits. (C) 2016 SAAB. Published by Elsevier B.V. All rights reserved

Drought and heat stability of the photosynthetic apparatus in bread wheat and in aegilops species

The responses of CO2 gas exchange, and heat stability were examined in two wheat (Triticum aestivum L.) cultivars and in Aegilops genotypes originating from habitats with different annual rainfalls and daily temperatures. Desiccation in soil pots resulted in moderate water loss in Ae. biunciais MvGB 377, 382 and Ae. bicornis MvGB 585, parallel with a high degree of stomatal closure and significant decrease in the net CO2 fixation (A), while in Ae. tauschii MvGB 605, 589 stomatal conductance (gs) and A remained relatively high in the desiccation period, and parallel with this gs and A were more tolerant to decrease in RWC than in wheat cultivars and in the above-detailed Aegilops genotypes. In spite of this, the decrease of RWC was fast and considerable in Ae. biuncialis MvGB 642, Ae. speltoides MvGB 1042, 624, and in Ae. tauschii MvGB 426 with a low degree of stomatal closure but A was more tolerant to water loss, especially in Ae. speltoides MvGB 1042. On the other hand, higher water deficit (RWC ~75%, 10-14 days drought treatment) resulted in a significant increase in the thermal stability of PS II for wheat and for some Aegilops genotypes. The results indicate that some Aegilops genotypes originating from arid habitats have better drought and desiccation induced heat tolerance than wheat, making them appropriate for improving the heat tolerance of wheat to survive dry and hot periods in the field. Keywords: drought stress, thermal tolerance, photosynthesis, wheat, Aegilops sp