Synthesis and Antiparasitic Activity of New Conjugates—Organic Drugs Tethered to Trithiolato-Bridged Dinuclear Ruthenium(II)–Arene Complexes

Tethering known drugs to a metalorganic moiety is an efficient approach for modulating the anticancer, antibacterial, and antiparasitic activity of organometallic complexes. This study focused on the synthesis and evaluation of new dinuclear ruthenium(II)–arene compounds linked to several antimicrobial compounds such as dapsone, sulfamethoxazole, sulfadiazine, sulfadoxine, triclosan, metronidazole, ciprofloxacin, as well as menadione (a 1,4‐naphtoquinone derivative). In a primary screen, 30 compounds (17 hybrid molecules, diruthenium intermediates, and antimicrobials) were assessed for in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β‐galactosidase (T. gondii β‐gal) at 0.1 and 1 μM. In parallel, the cytotoxicity in noninfected host cells (human foreskin fibroblasts, HFF) was determined by an alamarBlue assay. When assessed at 1 μM, five compounds strongly impaired parasite proliferation by >90%, and HFF viability was retained at 50% or more, and they were further subjected to T. gondii β‐gal dose‐response studies. Two compounds, notably 11 and 13, amide and ester conjugates with sulfadoxine and metronidazole, exhibited low IC50 (half‐maximal inhibitory concentration) values 0.063 and 0.152 μM, and low or intermediate impairment of HFF viability at 2.5 μM (83 and 64%). The nature of the anchored drug as well as that of the linking unit impacted the biological activity

New Nucleic Base-Tethered Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Compounds: Synthesis and Antiparasitic Activity

Aiming toward compounds with improved anti-Toxoplasma activity by exploiting the parasite auxotrophies, a library of nucleobase-tethered trithiolato-bridged dinuclear ruthenium(II)-arene conjugates was synthesized and evaluated. Structural features such as the type of nucleobase and linking unit were progressively modified. For comparison, diruthenium hybrids with other type of molecules were also synthesized and assessed. A total of 37 compounds (diruthenium conjugates and intermediates) were evaluated in a primary screening for in vitro activity against transgenic Toxoplasma gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in non-infected host cells (human foreskin fibroblasts, HFF) was determined by alamarBlue assay. Twenty compounds strongly impairing parasite proliferation with little effect on HFF viability were subjected to T. gondii β-gal half maximal inhibitory concentration determination (IC50) and their toxicity for HFF was assessed at 2.5 µM. Two promising compounds were identified: 14, ester conjugate with 9-(2-oxyethyl)adenine, and 36, a click conjugate bearing a 2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl substituent, with IC50 values of 0.059 and 0.111 µM respectively, significantly lower compared to pyrimethamine standard (IC50 = 0.326 µM). Both 14 and 36 exhibited low toxicity against HFF when applied at 2.5 µM and are candidates for potential treatment options in a suitable in vivo model

Quality of Education in Romania. Case Study – School Results

Education is an important area of training the individual’s personality for a better individual life, contributes to the well-being of society by developing a set of skills that can be applied throughout life, can trigger the emergence of innovative ideas that benefit society as a whole. Lack of education creates problems such as domestic violence, poor health and especially low living standards. That is why without a good education, a better society cannot be formed. The quality of education is given by all the characteristics of the education system. One of the indicators that can highlight the quality of education is represented by the students’ school results. Therefore, the emphasis is on students’ results and the added value of the school. „Education is increasingly becoming a public service, a provider of quality, which is evaluated and self-evaluated as an organization, based on standards and whose management must ensure the satisfaction of customer requirements, in terms of efficiency and maximizing added value ( Preda & Diaconescu, 2013, p.5). Quality in the educational environment is a mirror of performance in knowledge-based educational institutions that tend to be compatible with education systems around the world. And lack of education is a root cause of poverty

Improvement of optical properties by fluorescein complexation with Nano-Pt- and Nano-Ag - porphyrin hybrids

Hybrid organic-inorganic nanomaterials based on Pt and Ag colloids, namely nanoAg-5,10,15,20-tetrakis-(4-aminophenyl)-porphyrin-Zn(II) (ZnTAPP-AgNPs) and nano-Pt5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin-Zn(II) tetrachloride (ZnTMePyP-PtNPs) were obtained and their capacity to form improved optically active complexes with fluorescein was investigated. By interaction with minute quantities of fluorescein the intensity of absorption of the plasmonic bands of the ZnTAPP-AgNPs and ZnTMePyP-PtNPs hybrids increases. ZnTMePyP-PtNPs hybrid will be further tested in clinical trials because it allows for a larger concentration domain of fluorescein complexation and more accurate dosage. All the sensitive materials are easy to prepare and respect the rules of sustainable chemistry

Orange and lemon peel powders as a bioelement source

The purpose of this paper was to evaluate the concentration of some bioelements from citrus peel powder. Peels powder was obtained by drying and grinding citrus peels as a by-product resulting after the preparation of some natural juices. The results obtained by atomic absorption spectrometry of Na, K, Ca, Mg, Fe, Mn, Zn and Cu, shows that the powders taken into the study contain important amounts of essential mineral elements, especially Ca and K (159-182 mg/100g, respectively 211-218 mg/100g) and also appreciable contents of Mg (15.3-23.4 mg/100g), Fe (18.1-34.1 mg/100g), Zn (9.34-11.8 mg/100g), Na (8.75-12.8 mg/100g), Cu (1.27-3.71 mg/100g) and Mn (1.32-2.03 mg/100g). The concentration of the analyzed mineral bioelements shows, in general, the following decreasing trend: K> Ca> Fe> Mg> Zn> Na> Cu> Mn

Medicinal plants - important source of essential microelements

The purpose of this paper was to evaluate the concentration of some essential microelements (Fe, Mn, Zn and Cu) from the leaves of two plants: stinging nettle (Urtica dioica) and sage (Salvia officinalis), species of plants with multiple uses in the food and medical field due to their high content of compounds with beneficial action for organisms. Samples were obtained by washing, drying and calcination of fresh leaves. The results obtained by atomic absorption spectrometry regarding Mn, Fe, Zn and Cu concentration in sage and nettle leaves shows that the samples contains important amounts of essential microelements, Cu (1.72-1.87 mg/g), Fe (25.43-65.67 mg/g), Mn (7.86 – 9.30 mg/g), Zn (54.61 – 73.12 mg/g). The appreciable contents of essential microelements recommend the use of these plants as a supplementary source of essential elements

In Vitro versus in Mice: Efficacy and Safety of Decoquinate and Quinoline-O-Carbamate Derivatives against Experimental Infection with Neospora caninum Tachyzoites.

The effects of decoquinate (DCQ) and three O-quinoline-carbamate-derivatives were investigated using human foreskin fibroblasts (HFF) infected with Neospora caninum tachyzoites. These compounds exhibited half-maximal proliferation inhibition (IC50s) from 1.7 (RMB060) to 60 nM (RMB055). Conversely, when applied at 5 (DCQ, RMB054) or 10µM (RMB055, RMB060), HFF viability was not affected. Treatments of infected cell cultures at 0.5µM altered the ultrastructure of the parasite mitochondrion and cytoplasm within 24 h, most pronounced for RMB060, and DCQ, RMB054 and RMB060 did not impair the viability of splenocytes from naïve mice. Long-term treatments of N. caninum-infected HFF monolayers with 0.5µM of each compound showed that only exposure to RMB060 over a period of six consecutive days had a parasiticidal effect, while the other compounds were not able to kill all tachyzoites in vitro. Thus, DCQ and RMB060 were comparatively assessed in the pregnant neosporosis mouse model. The oral application of these compounds suspended in corn oil at 10 mg/kg/day for 5 d resulted in a decreased fertility rate and litter size in the DCQ group, whereas reproductive parameters were not altered by RMB060 treatment. However, both compounds failed to protect mice from cerebral infection and did not prevent vertical transmission/pup mortality. Thus, despite the promising in vitro efficacy and safety characteristics of DCQ and DCQ-derivatives, proof of concept for activity against neosporosis could not be demonstrated in the murine model

The Impact of BKI-1294 Therapy in Mice Infected With the Apicomplexan Parasite Neospora caninum and Re-infected During Pregnancy.

Exposure of Neospora caninum tachyzoites to BKI-1294 in vitro results in the formation of long-lived multinucleated complexes (MNCs). However, in vivo treatment of BALB/c mice with BKI-1294 shortly after N. caninum infection during pregnancy was safe and profoundly reduced pup mortality and vertical transmission. We hypothesized that the formation of MNCs could trigger immune responses that contribute to BKI efficacy in vivo. In this study, mice were first vaccinated with a sublethal dose of N. caninum tachyzoites and were treated with BKI-1294. We then investigated the effects of these treatments after mating and re-infection during pregnancy. Effects on fertility, pup survival, vertical transmission, and parasite load in dams were evaluated. Cytokines in sera or splenocyte culture supernatants were assessed by either ELISA or the Luminex™ 200 system, and humoral immune responses against tachyzoite and MNC antigens were compared by ELISA, Western blotting and immunoproteomics. Our results showed that BKI-1294 treatment of live-vaccinated mice reduced the cerebral parasite load in the dams, but resulted in higher neonatal pup mortality and vertical transmission. In live-vaccinated mice, cytokine levels, most notably IFN-y, IL-10, and IL-12, were consistently lower in BKI-1294 treated animals compared to non-treated mice. In addition, comparative Western blotting identified two protein bands in MNC extracts that were only recognized by sera of live-vaccinated mice treated with BKI-1294, and were not found in tachyzoite extracts. We conclude that treatment of live-vaccinated mice with BKI-1294 influenced the cellular and humoral immune responses against infection, affected the safety of the live-vaccine, and decreased protection against re-infection and vertical transmission during pregnancy

Common Molecular Targets of a Quinolone Based Bumped Kinase Inhibitor in Neospora caninum and Danio rerio.

Neospora caninum is an apicomplexan parasite closely related to Toxoplasma gondii, and causes abortions, stillbirths and/or fetal malformations in livestock. Target-based drug development has led to the synthesis of calcium-dependent protein kinase 1 inhibitors, collectively named bumped kinase inhibitors (BKIs). Previous studies have shown that several BKIs have excellent efficacy against neosporosis in vitro and in vivo. However, several members of this class of compounds impair fertility in pregnant mouse models and cause embryonic malformation in a zebrafish (Danio rerio) model. Similar to the first-generation antiprotozoal drug quinine, some BKIs have a quinoline core structure. To identify common targets in both organisms, we performed differential affinity chromatography with cell-free extracts from N. caninum tachyzoites and D. rerio embryos using the 5-aminopyrazole-4-carboxamide (AC) compound BKI-1748 and quinine columns coupled to epoxy-activated sepharose followed by mass spectrometry. BKI-binding proteins of interest were identified in eluates from columns coupled to BKI-1748, or in eluates from BKI-1748 as well as quinine columns. In N. caninum, 12 proteins were bound specifically to BKI-1748 alone, and 105 proteins, including NcCDPK1, were bound to both BKI-1748 and quinine. For D. rerio, the corresponding numbers were 13 and 98 binding proteins, respectively. In both organisms, a majority of BKI-1748 binding proteins was involved in RNA binding and modification, in particular, splicing. Moreover, both datasets contained proteins involved in DNA binding or modification and key steps of intermediate metabolism. These results suggest that BKI-1748 interacts with not only specific targets in apicomplexans, such as CDPK1, but also with targets in other eukaryotes, which are involved in common, essential pathways