Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model

Plasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent

MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation

Hypermethylation of the MGMT gene promoter and mutation of the TP53 tumor-suppressor gene are frequently present in diffuse astrocytomas. However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII) to anaplastic astrocytoma (AIII) and secondary glioblastoma (sGB). In this study biopsy specimens from 51 patients with astrocytic tumors with radiologically proved progression from low to high-grade malignancy were investigated for the presence and consistency of MGMT promoter hypermethylation and TP53 mutations. For 27 patients biopsy samples both of primary tumors and their recurrences were available. For the other 24 patients histology of either the low-grade lesion or the high-grade recurrence was available. It was found that MGMT promoter hypermethylation and TP53 mutations are both frequent and early events in the progression of astrocytomas and that their status is consistent over time. No correlation was found between MGMT methylation status and the presence of TP53 mutations. In addition, no correlation was found between MGMT promoter hypermethylation and the type of TP53 mutations. These results argue against the putative TP53 G:C>A:T transition mutations suggested to occur preferentially in MGMT hypermethylated tumors

Resistance to paclitaxel in a cisplatin-resistant ovarian cancer cell line is mediated by P-glycoprotein

The IGROVCDDP cisplatin-resistant ovarian cancer cell line is also resistant to paclitaxel and models the resistance phenotype of relapsed ovarian cancer patients after first-line platinum/taxane chemotherapy. A TaqMan low-density array (TLDA) was used to characterise the expression of 380 genes associated with chemotherapy resistance in IGROVCDDP cells. Paclitaxel resistance in IGROVCDDP is mediated by gene and protein overexpression of P-glycoprotein and the protein is functionally active. Cisplatin resistance was not reversed by elacridar, confirming that cisplatin is not a P-glycoprotein substrate. Cisplatin resistance in IGROVCDDP is multifactorial and is mediated in part by the glutathione pathway and decreased accumulation of drug. Total cellular glutathione was not increased. However, the enzyme activity of GSR and GGT1 were up-regulated. The cellular localisation of copper transporter CTR1 changed from membrane associated in IGROV-1 to cytoplasmic in IGROVCDDP. This may mediate the previously reported accumulation defect. There was decreased expression of the sodium potassium pump (ATP1A), MRP1 and FBP which all have been previously associated with platinum accumulation defects in platinum-resistant cell lines. Cellular localisation of MRP1 was also altered in IGROVCDDP shifting basolaterally, compared to IGROV-1. BRCA1 was also up-regulated at the gene and protein level. The overexpression of P-glycoprotein in a resistant model developed with cisplatin is unusual. This demonstrates that P-glycoprotein can be up-regulated as a generalised stress response rather than as a specific response to a substrate. Mechanisms characterised in IGROVCDDP cells may be applicable to relapsed ovarian cancer patients treated with frontline platinum/taxane chemotherapy

Antimicrobial activity of potato juice

Doniesienia literaturowe wskazują, że sok z ziemniaków może być cennym źródłem związków bioaktywnych korzystnie oddziałujących na organizm człowieka. Jak dotąd nie scharakteryzowano jednak w pełni aktywności przeciwdrobnoustrojowej tego produktu. Dlatego też, w niniejszej pracy oceniono aktywność przeciwdrobnoustrojową suszu soku ziemniaczanego powstałego w procesie suszenia rozpyłowego oraz sublimacyjnego, jego hydrolizatu oraz frakcji odbiałczonej. W testach bioaktywności zastosowano szczepy bakterii z rodzajów: Bacteroides, Listeria, Salmonella, Clostridium, Escherichia, Enterococcus, Lactobacillus,, Staphylococcus, Yersinia oraz drożdże Candida i Saccharomyces. Aktywność przeciwdrobnoustrojową oznaczano metodą punktowo-dyfuzyjną. Dodatkowo zbadano zawartość glikoalkaloidów, mikro- i makroelementów, witamin z grupy B oraz witaminy C w soku z ziemniaków, a także podjęto pró- bę określenia ich wpływu na bioaktywność. Przeprowadzone badania wykazały, że żaden z zastosowanych preparatów niezależnie od składu chemicznego i sposobu wytworzenia nie wykazywał aktywności antagonistycznej w stosunku do mikroorganizmów patogennych, probiotycznych i komensalych.There are information in the literature that potato juice could be a valuable source of bioactive compounds revealing beneficial effect on the human health. However, the antimicrobial activity on this product has not been fully established so far. The aim of this study was to evaluate the antimicrobial activity of dried potato juice obtained by spray or sublimation drying, as well as products of its enzymatic hydrolysis and deproteinization. The bacteria of the genera Bacteroides Listeria, Salmonella, Clostridium, Escherichia, Enterococcus, Lactobacillus, Staphylococcus, Yersinia as well as yeasts: Candida and Saccharomyces were used in the study. Antimicrobial activity was determined using the spot-diffusion method. Additionally, characterization of the juice in terms the content of glycoalkaloids, vitamins C and the B group, as well as micro-and macroelements was made. The study showed that none of the investigated species had activity against all pathogenic, commensal and probiotic microflora

Charakterystyka struktury, wlasciwosci fizykochemiczne i mozliwosci zastosowania skrobi amarantusa

The potential uses of amaranth (Amaranthus hypochondriacus) starch from the species grown in Poland were recognized by determining the basic physico- chemical properties and functionality in mayonnaise and glue systems. Rheological methods, scanning electron microscopy, and light microscopy were employed in the analysis of isolated starch. When used in low-fat mayonnaise formulas, the amaranth starch gave them excellent organoleptic qualities, but rather poor rheological stability. The amaranth starch also showed great use value as a major component of corrugated-board glues.Celem pracy było poznanie podstawowych właściwości fizykochemicznych, mikrostruktury i możliwości zastosowania skrobi Amaranthus hypochondriacus gatunku uprawianego w Polsce. Metoda Myersa i Foxa umożliwiła wyizolowanie z nasion amarantusa skrobi 0 bardzo wysokim stopniu czystości, o niskiej zawartość tłuszczu (0.27%) i białka (0.53%), w postaci bardzo małych, niezwykle wyrównanych pod względem wielkości ziarenek skupionych w większe aglomeraty liczące kilka tysięcy pojedynczych granulek (fot. 1-3). Należy zwrócić uwagę na bardzo niską zawartość amylozy co pozwala zakwalifikować tę skrobię do gatunków woskowych. Skleikowana skrobia amarantusa wykazuje wysoką rozpuszczalność i stosunkowo niską siłę pęcznienia (tab. 1). Przebieg kleikowania charakteryzuje się niską temperaturą kleikowania w połączeniu z dużą stabilnością reologiczną podczas inkubacji i schładzania (rys.1). Skrobia amarantusa reaguje na zmiany temperatury słabiej niż skrobia kukurydziana i nie wykazuje tendencji do żelowania w całym zakresie pomiarowym (rys. 2). Takie zachowanie może być bardzo pożądaną cechą, zwłaszcza w przemyśle spożywczym. Zmiany struktury kleików podczas ogrzewania przedstawione na fot. 4 (SEM) i fot. 5 (LM) potwierdzają łatwość kleikowania skrobi amarantusa. Zbadano przydatność skrobi amarantusa jako środka zagęszczająco-stabilizującego w produkcji majonezów nisko-tłuszczowych i stwierdzono, że nadaje im znakomite własności sensoryczne nie zapewniając jednak trwałości reologicznej (rys. З i 4). Bardzo mały i wyrównany rozmiar ziarenek zasugerował możliwość niespożywczego wykorzystanie skrobi amarantusa. Uzyskane wyniki (tab. 2) potwierdziły, że w postaci natywnej stanowi ona doskonały surowiec do produkcji kleju do tektury falistej (opakowania biodegradowalne)