IGFs and IGF-Binding Proteins in the Synovial Fluid of Patients with Rheumatoid Arthritis and Osteoarthritis

International Journal of Peptide Research and Therapeutics - The progressive damage of human articular cartilage is associated with loss of integrity of its extracellular matrix components. Their...     

Inhibitory Effect of Eugenol and trans-Anethole Alone and in Combination with Antifungal Medicines on Candida albicans Clinical Isolates

One of the most common pathogens among yeasts is Candida albicans, which presents a serious health threat. The study aimed to check the antifungal properties of trans-anethole and eugenol with selected antifungal medicines (AMs) against C. albicans clinical isolates. The checkerboard method was used to tests of interactions between these compounds. Achieved results indicated that eugenol showed synergistic and additive activities with miconazole and econazole against investigated clinical isolates, respectively. Moreover, the combination – trans-anethole – miconazole also showed an additive effect against two clinical isolate. We tried to relate the results to changes in C. albicans cell sheaths under the influence of essential oils compounds (EOCs) performing the Fourier transform infrared spectra analysis to confirm the presence of particular chemical moieties in C. albicans cells. Nevertheless, no strong relationships was observed between synergistic and additive actions of used EOC-AMs combinations and chemical moieties in C. albicans cells.     

Teriflunomide – The common drug with underestimated oxygen - Dependent anticancer potential

Leflunomide (LFN) is a well-known immunomodulatory and anti-inflammatory prodrug of teriflunomide (TFN). Due to pyrimidine synthesis inhibition TFN also exhibits potent anticancer effect. Because, there is the strict coupling between the pyrimidine synthesis and the mitochondrial respiratory chain, the oxygen level could modify the cytostatic TNF effect.The aim of the study was to evaluate the cytostatic effect of pharmacologically achievable teriflunomide (TFN) concentrations at physiological oxygen levels, i.e. 1% hypoxia and 10% tissue normoxia compared to 21%oxygen level occurred in routine cell culture environment.The TFN effect was evaluated using TB, MTT and FITC Annexin tests for human primary (SW480) and metastatic (SW620) colon cancer cell lines at various oxygen levels.We demonstrated significant differences between proliferation, survival and apoptosis at 1, 10 and 21% oxygen in primary and metastatic colon cancer cell lines (SW480, SW620) under TFN treatment. The cytostatic TFN effect was more pronounced at hypoxia compared to tissue and atmospheric normoxia in both cancer cell lines, however metastatic cells were more resistant to antiproliferative and proapoptotic TFN action. The early apoptosis was predominant in physiological oxygen tension while in atmospheric normoxia the late apoptosis was induced.Our findings showed that anticancer TFN effect is more strong in physiological oxygen compared to atmospheric normoxia. It suggests that results obtained from in vitro studies could be underestimated. Thus, it gives assumption for future comprehensive studies at real oxygen environment involving TNF use in combination with other antitumor agents affecting oxygen-dependent pyrimidine synthesis.     

Structural damages in adsorbed vaccines affected by freezing

This study was planned to evaluate structural damages in adsorbed vaccines affected by freezing using scanning electron microscopy and X-ray analysis of the elements. Randomly selected 42 vials of eight different types of WHO pre-qualified adsorbed freeze-sensitive vaccines from 10 manufacturers were included in the study. Vaccines were kept at 5 °C. Selected numbers of vials from each type were then exposed to ?25 °C for 24 h periods. All samples were evaluated for their structure using scanning electron microscopy, X-ray analysis of the elements and precipitation time. Scanning electron microscopy of vaccines affected by freezing showed either smooth or rough surfaced conglomerates associated with phosphate content of the precipitate. These vaccines precipitated 2–15 times faster compared to non-frozen samples. Non-frozen samples showed uniform flocculent structure either dense or dispersed. X-ray analysis of precipitates in frozen samples confirmed that the precipitate is mainly aluminium clutters. Scanning electron microscopy confirmed that the lattice structure of bonds between adsorbent and the antigen is broken and aluminium forms conglomerates that grow in size and weight. The precipitation time of vaccines affected by freezing is 4.5 times faster on average compared to non-frozen samples. These facts form the basis of the "shake test".     

TNP-470 Inhibits Oxidative Stress,Nitric Oxide Production and Nuclear Factor Kappa B Activation in a Rat Model of Hepatocellular Carcinoma

The objective of this study is to determine if treatment with the angiogenesis inhibitor TNP-470 results in impairment of oxidative stress, inhibition of nuclear factor kappa B (NF-κB) activation and decrease of nitric oxide production in an experimental model of rat hepatocarcinogenesis. Tumour was induced by diethylnitrosamine and promoted by two-thirds hepatectomy plus acetaminofluorene administration. Experiments were carried out at 28 weeks after initiating the treatment. TNP-470 was administered at 30 mg/kg, three times per week from 20 to 28 weeks. Carcinomatous tissue growing outside dysplastic nodules and a marked expression of placental glutathione S-transferase were detected in rats with induced carcinogenesis. Liver concentrations of thiobarbituric acid reactive substances, reduced glutathione (GSH) and glutathione disulfide (GSSG) were significantly higher than those of controls and there was a significant increase in the GSSG/GSH ratio. Tumour growth was accompanied by augmented expression of inducible nitric oxide synthase, activation of (NF-κB) and proteolysis of IkappaB. All these effects were absent in animals receiving TNP-470. Our results indicate that TNP-470 inhibits oxidative stress, nitric oxide production and NF-κB activation induced by experimental hepatocarcinogenesis. These changes would contribute to the beneficial effects of TNP-470 in cancer treatment.     

Interactions of vasopressin and oxytocin receptors with vasopressin analogues substituted in position 2 with 3,3′‐diphenylalanine – a molecular docking study

Vasopressin and oxytocin receptors belong to the superfamily of G protein‐coupled receptors and play an important role in many physiological functions. They are also involved in a number of pathological conditions being important drug targets. In this work, four vasopressin analogues substituted at position 2 with 3,3′‐diphenylalanine have been docked into partially flexible vasopressin and oxytocin receptors. The bulky residue at position 2 acts as a structural restraint much stronger in the oxytocin receptor (OTR) than in the vasopressin V2 receptor (V2R), resulting in a different location of the analogues in these receptors. This explains the different, either agonistic or antagonistic, activities of the analogues in V2R and OTR, respectively. In all complexes, the conserved polar residues serve as anchor points for the ligand both in OTR and V2R. Strong interactions of the C‐terminus of analogue II ([Mpa¹,d ‐Dpa²,Val⁴,d ‐Arg⁸]VP) with extracellular loop 3 may be responsible for its highest activity at V2R. It also appears that V2R adapts more readily to the docking analogues by conformational changes in the aromatic side chains triggering receptor activation. A weak activity at V1a vasopressin receptor appears to be caused by weak receptor–ligand interactions. Results of this study may facilitate a rational design of new analogues with the highest activity/selectivity at vasopressin and OTRs. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd.     

New Strategies for Chemical Synthesis of Phosphorodithioates Derived from 2′- or 3′- or 5′-Thionucleosides

Abstract

Various phophorodithioates derived from thionucleosides were synthesis by the reaction anhydronucleosides with phosphorodithioic acids     

Efficient Synthesis of 2′-Deoxynucleoside 3′-C-Phosphonates: Reactivity of Geminal Hydroxyphosphonate Moiety

Abstract

In this report we present a novel, simple way for the synthesis of 3′-C-phosphonate derivatives of all four basic 2′-deoxynucleosides in both fully protected and deprotected forms. The reactivity of the geminal hydroxy phosphonate moiety located at the 3′-carbon atom of the nucleoside was studied with respect to the use of this type of nucleoside phosphonic acid for the preparation of short oligonucleotides, namely, dinucleoside monophosphate analogues.     

Transgenic pigs designed to express human α-galactosidase to avoid humoral xenograft rejection

The use of animals as a source of organs and tissues for xenotransplantation can overcome the growing shortage of human organ donors. However, the presence of xenoreactive antibodies in humans directed against swine Gal antigen present on the surface of xenograft donor cells leads to the complement activation and immediate xenograft rejection as a consequence of hyperacute reaction. To prevent hyperacute rejection, it is possible to change the swine genome by a human gene modifying the set of donor’s cell surface proteins. The gene construct pGal-GFPBsd containing the human gene encoding α-galactosidase enzyme under the promoter of EF-1α elongation factor ensuring systemic expression was introduced by microinjection into a male pronucleus of the fertilised porcine oocyte. As a result, the founder male pig was obtained with the transgene mapping to chromosome 11p12. The polymerase chain reaction (PCR) analysis revealed and the Southern analysis confirmed transgene integration estimating the approximate number of transgene copies as 16. Flow cytometry analysis revealed a reduction in the level of epitope Gal on the cell surface of cells isolated from F0 and F1 transgenic animals. The complement-mediated cytotoxicity assay showed increased viability of the transgenic cells in comparison with the wild-type, which confirmed the protective influence of α-galactosidase expression.     

Molecular diagnosis of cystic echinococcosis in humans from central Poland

The identity of the causative agent of cystic echinococcosis (CE) in humans from central Poland receiving treatment between 2000 and 2010 was determined. A total of 47 samples obtained after hepatectomy were examined and protoscoleces were identified in wet preparations in 27 cases. Using DNA extracted from the samples, two mitochondrial regions (nad1 and cox1 genes) were amplified and the nad1 fragment was sequenced. This PCR analysis confirmed the presence of Echinococcus species in 30 cases and nad1 sequence alignments showed identity with the G7 (pig) strain, Echinococcus canadensis. These data demonstrate that the pig strain of this parasite is the most frequent causative agent of human cystic echinococcosis in central Poland.