Cationic amphiphilic drugs as potential anticancer therapy for PDAC

Part of special issue: 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Barcelona, Spain 28 October 2022 10:00–15:00: POSTER SESSION: Drug Screenin

Svojstva prestižnih samooplodnih linija kukuruza relevantna za savremenu proizvodnju kvalitetnog hibridnog semena

The obtained results confirm the hypothesis that there are maize elite inbred lines (ZPPL 62 and ZPPL 233) that are considered prestigious and are characteristic by their water status and a greater rate of a dry down during the grain maturation. Also, they are characteristic by their efficient photosynthetic-fluorescence photo-model, which is successfully used in the contemporary technological productions of maize hybrid seed. The presented results on the dynamics of grain dry down during the maturation period and on photosynthetic and fluorescence parameters: temperature dependency of the intensity of delay chlorophyll fluorescence, the Arrhenius plot for the determination of critical temperatures (phase transition temperatures), activation energy and the angle between the ear leaf and the stalk of the maize plant, show that traits of observed inbreds are mainly based on good effects and nature of conformational and functional changes that occur in their thylakoid membranes and other chemical structures of grain and leaf tissue. Some other properties of observed prestigious maize inbred lines relevant to the seed production were also analyzed in this study.U ovom radu potvrđuje se hipoteza da postoje elitne samooplodne linije kukuruza koje se smatraju prestižnim i koje poseduju, kako svojstvo stanja vode i njenog bržeg otpuštanja iz zrna u periodu sazrevanja, tako i svojstvo efikasnog fotosintetično-fluorescentnog fotomodela, koji se uspešno koristi u savremenim tehnologijama proizvodnje hibridnog semena kukuruza. Izloženi rezultati o dinamici otpuštanja vode iz zrna u periodu sazrevanja i o fotosintetično-fluorescentnim pokazateljima: teperaturnoj zavisnosti intenziteta zakasnele fluorescencije hlorofila, Arenijusovim kriterijumom za određivanje kritičnih temperatura (temperature faznih prelaza), energija aktivacije i veličine ugla između lista na klipu i stabljike kukuruza, pokazuju da su svojstva proučavanih linija zasnovana na dobrim efektima i prirodi strukturnih i funkcionalnih promena, koje se odigravaju u njihovim tilakoidnim membranama i drugim hemijskim strukturama tkiva zrna i lista. U radu se analiziraju i druge relevantne semenarske karakteristike proučavanih prestižnih samooplodnih linija kukuruza

Late neolithic and early eneolithic figurative sculpture from the northern of the central Balkans

Figurines stand out as one of the most remarkable features of Neolithic material culture, reflecting the image of Neolithic man and his style of life in a very direct and impressive way. Through various forms and stylizations, figurines reveal details about the clothing, adornment, hairstyle or physical appearance of an individual, while their functional and spiritual character remains a burning issue in archaeological debates. In European Neolithic era, the culture of Vinča stands out as the one characterized by superior craftsmenship in clay modeling, its most prominent aspect being figurative sculpture, one of the most outstanding artistic achievements of the Neolithic era. Although figurative sculpture is present in all phases of Vinča culture (5400- 4500 BC), it could be claimed that its diversity, profusion and high artisanship culminated in the centuries around 4800 BC (Тасић 2008: 144). It is assumed that such flourishing of art is connected with the continual existence of the settlements and stable economy, followed by an organized social system with a developed belief system and established ritual practices. The sample chosen for the statistical analysis of the sex or any other detail is limited to the specimens with preserved body parts on which it is possible to notice the existence of the required element. Thus, if we are interested in the sex of the figurine, the analytical sample will only be comprised of the specimens with preserved body parts on which sex attributes could be expected. The procedure is similar if we are interested in the number of bracelets shown on female figurines, in which case the sample will include only the specimens with defined sex and at least one preserved arm. Such sampling procedure was followed consistently in all the statistical analyses of the presence of certain elements on the figurines. The total of Neolithic and early Eneolithic figurines from northern areas of the Central Balkans is 359 specimens of figurative sculpture, collected from fifteen sites from four narrow geographical areas, marked as Župa aleksandrovačka, lower section of Južna Morava, Ponišavlje and Toplica

Aktuelna prestižna svojstva samooplodnih linija kukuruza - dobra polazna osnova za efikasno kreiranje novih i rodnih hibrida kukuruza

This study conforms our hypothesis that there are elite maize inbred lines, which can be considered actual and prestigious as they have not only a property of the water status and a greater grain dry down rate during the maturation period, but also a property of the efficient photosynthetic-fluorescence model that is successfully used in the contemporary processes of breeding, and thereby in the development of new and yielding maize hybrids. Presented results obtained on the dynamics of grain dry down during the maturation period and on photosynthetic-fluorescence parameters (temperature dependence of the chlorophyll delayed fluorescence intensity, the Arrhenius plot for the determination of critical temperatures, i.e. phase transition temperatures and the activation energy) show that properties of the observed inbreeds are based on effects and nature of conformational and functional changes occurring in their thylakoid membranes and other chemical structures of grain tissues. Summarized results of studies on actual and prestigious properties of maize inbreeds will contribute to more exact, rational and expeditious proceedings of contemporary processes of breeding.Idejom za ovaj rad potvrđuje se naša hipoteza da postoje elitne linije kukuruza koje se smatraju aktuelnim i prestižnim i koje poseduju, kako svojstvo stanja vode i njenog bržeg otpuštanja iz zrna u periodu sazrevanja, tako i svojstvo efikasnog fotosintetično-fluorescentnog modela, koji se uspešno koristi u savremenim procesima oplemenjivanja, a time i za stvaranje novih i rodnijih hibrida kukuruza. Izloženi rezultati o dinamici otpuštanja vode iz zrna u periodu sazrevanja i o fotosintetično-fluorescentnim pokazateljima: teperaturnoj zavisnosti intenziteta zakasnele fluorescencije hlorofila, Arrhenijus-ovim kriterijumom za određivanje kritičnih temperatura i energija aktivacije, pokazuju da su svojstva proučavanih linija zasnovana na efektima i prirodi strukturnih i funkcionalnih promena koje se odigravaju u njihovim tilakoidnim membranama i drugim hemijskim strukturama tkiva zrna. Sumarni rezultati proučavanja aktuelnih i prestižnih svojstava linija kukuruza doprineće egzaktnijem, racionalnijem i bržem odvijanju savremenih procesa oplemenjivanja

Effects of Vitamin D3 on the NADPH Oxidase and Matrix Metalloproteinase 9 in an Animal Model of Global Cerebral Ischemia.

Decreased blood flow in the brain leads to a rapid increase in reactive oxygen species (ROS). NADPH oxidase (NOX) is an enzyme family that has the physiological function to produce ROS. NOX2 and NOX4 overexpression is associated with aggravated ischemic injury, while NOX2/4-deficient mice had reduced stroke size. Dysregulation of matrix metalloproteinases (MMPs) contributes to tissue damage. The active form of vitamin D3 expresses neuroprotective, immunomodulatory, and anti-inflammatory effects in the CNS. The present study examines the effects of the vitamin D3 pretreatment on the oxidative stress parameters and the expression of NOX subunits, MMP9, microglial marker Iba1, and vitamin D receptor (VDR), in the cortex and hippocampus of Mongolian gerbils subjected to ten minutes of global cerebral ischemia, followed by 24 hours of reperfusion. The ischemia/reperfusion procedure has induced oxidative stress, changes in the expression of NOX2 subunits and MMP9 in the brain, and increased MMP9 activity in the serum of experimental animals. Pretreatment with vitamin D3 was especially effective on NOX2 subunits, MMP9, and the level of malondialdehyde and superoxide anion. These results outline the significance of the NOX and MMP9 investigation in brain ischemia and the importance of adequate vitamin D supplementation in ameliorating the injury caused by I/R

Unveiling the 4-aminoquinoline derivatives as potent agents against pancreatic ductal adenocarcinoma (PDAC) cell lines

Common antimalarials such as artemisinins, chloroquine and their derivatives also possess potent antiinflamantory, antiviral and anticancer properties. In the search for new therapeutics to combat difficult-totreat pancreatic carcinomas, we unveiled that 4-aminoquinoline derivatives, with significant antiplasmodialproperties and a great safety profile in vivo, have remarkable anticancer activity against pancreatic ductaladenocarcinoma (PDAC) and considerable efficacy in the xenograft model in vivo. The aim of the present studywas to further investigate anticancer properties of these compounds in a drug-repurposing manner. The compounds showed profound cytotoxic effects at nanomolar to low micromolar concentration in 2D cultured cells (invitro) and in the zebrafish PDAC xenograft model (in vivo). A deeper insight into their mechanisms of cytotoxicaction showed these compounds induce apoptosis while increasing reactive oxygen species levels along withautophagy inhibition. Additional investigation of the autophagy modulation proved that tested quinoline derivatives cause P62 and LC3-II accumulation in PDAC cells alongside lysosomal alkalinization. Further, in vivotoxicity studies in the zebrafish model showed low toxicity without developmental side effects of the investigated4-aminoquinolines, while the applied compounds effectively inhibited tumor growth and prevented the metastasis of xenografted pancreatic cells. Taken together, these results highlight the 4-aminoquinolines as privilegedstructures that ought to be investigated further for potential application in pancreatic carcinoma treatment.This is the peer-reviewed version of the article: Živanović, M., Selaković, M., Pavić, A., Selaković, Ž., Šolaja, B., Santibanez, J. F.,& Srdić-Rajić, T.. (2024). Unveiling the 4-aminoquinoline derivatives as potent agents against pancreatic ductal adenocarcinoma (PDAC) cell lines. in Chemico-Biological Interactions Elsevier., 404, 111281. [https://doi.org/10.1016/j.cbi.2024.111281

Poboljšani fotositetično-fluorescentni metod i njegova primena u oplemenjivanju i semenarstvu kukuruza

The application of the improved non-invasive photosynthetic-fluorescence method in maize breeding and seed production was observed in order to assess the resistance and adaptability of maize inbred lines to higher and high temperatures, as well as to drought. The studies were carried out with two maize inbred lines (ZPPL 115 and A 671). The thermal characteristics of the photosynthetic apparatus of the investigated maize inbred lines were determined as follows: temperature dependency range from 25 to 60oC, critical temperatures at which phase transitions take place in the thylakoid membrane, causing significant structural and functional changes in the photosynthetic apparatus of the investigated inbred lines, activation energies (Ea, kJ/mol) were calculated along the straight lines before and after the occurrence of the critical temperature. The activation energy (Ea) is a measure of the intensity of recombining responses to chlorophyll DF, and total changes in the structure and functioning of the thylakoid membranes. The results obtained and presented parameters of total photosynthetic and thermal processes of chlorophyll DF may contribute to a more accurate characterisation of maize inbred lines in respect to their resistance and adaptability to temperatures and drought. Consecutively, this can lead to a quicker and more rational improvement maize breeding and seed production.Poboljšani neinvazivni fotosintetično-fluorescentni metod kandiduje se za primenu u oplemenjivanju i semenarstvu radi utvrđivanja ocene samooplodnih linija kukuruza na plastičnost, tolerantnost, otpornost i adaptivnost prema višim i visokim temperaturama, kao i prema suši. Utvrđene su termalne karakteristike fotosintetičnog aparata proučavanih samooplodnih linija kukuruza, i to: određena je temperaturna zavisnost u opsegu od 25 do 60oC, otkrivene su kritične temperature na kojima dolazi do faznih transformacija u tilakoidnoj membrani, a time i do značajnih strukturnih i funkcionalnih promena u fotosintetičnom aparatu ispitivanih samooplodnih linija kukuruza, obračunate su energije aktivacije (Ea, kJ/mol) duž pravih linija pre i posle pojavljivanja kritične temperature. Energija aktivacije (Ea) je mera nastajanja rekombinacionih reakcija povezanih sa uspostavljanjem ZF hlorofila, a time i ukupnih promena u strukturi i funkciji tilakodinih membrana. Ostvareni rezultati i diskusija izloženih parametara ukupnih fotosintetično-termalnih procesa ZF hlorofila mogu doprineti egzaktnijem karakterisanju ispitivanih samooplodnih linija kukuruza u odnosu na njihovu plastičnost, tolerantnost, otpornost i adaptivnost prema temperaturi i suši, što samim tim i doprinosi bržem i racionalnijem unapređenju procesa selekcije i produktivne semenske proizvodnje

Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action

Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design, synthesis and anti-viral activities of two classes of compounds which show high potency against EBOV in both in vitro cell culture assays and in vivo mouse models Ebola viral disease. These compounds incorporate the structural features of cationic amphiphilic drugs (CAD), i.e they possess both a hydrophobic domain and a hydrophilic domain consisting of an ionizable amine functional group. These structural features enable easily diffusion into cells but once inside an acidic compartment their amine groups became protonated, ionized and remain trapped inside the acidic compartments such as late endosomes and lysosomes. These compounds, by virtue of their lysomotrophic functions, blocked EBOV entry. However, unlike other drugs containing a CAD moiety including chloroquine and amodiaquine, compounds reported in this study display faster kinetics of accumulation in the lysosomes, robust expansion of late endosome/lysosomes, relatively more potent suppression of lysosome fusion with other vesicular compartments and inhibition of cathepsins activities, all of which play a vital role in anti-EBOV activity. Furthermore, the diazachrysene 2 (ZSML08) that showed most potent activity against EBOV in in vitro cell culture assays also showed significant survival benefit with 100% protection in mouse models of Ebola virus disease, at a low dose of 10 mg/kg/day. Lastly, toxicity studies in vivo using zebrafish models suggest no developmental defects or toxicity associated with these compounds. Overall, these studies describe two new pharmacophores that by virtue of being potent lysosomotrophs, display potent anti-EBOV activities both in vitro and in vivo animal models of EBOV disease