Target fishing and docking studies of the novel derivatives of aryl-aminopyridines with potential anticancer activity

A set of 16 previously synthesized aryl-aminopyridine and aryl-aminoquinoline derivatives have been evaluated for cytotoxic activity against three cancer cell lines (human cervical cancer-HeLa; human chronic myeloid leukemia-K562; human melanoma-Fem-x) and two types of normal peripheral blood mononuclear cells, with and without phytohemaglutinin (PBMC-PHA; PBMC+PHA). Twelve of the studied compounds showed moderate cytotoxicity, with selectivity against K562 but not the remaining two cancer cell lines. Four compounds were not active in cytotoxicity assays, presumably due to high predicted lipophilicity and low solubility. To rationalize the observed cytotoxic effects, structure-based virtual screening was carried out against a pool of potential targets constructed using the inverse docking program Tarfisdock and bibliographical references. The putative targets were identified on the basis of the best correlation between docking scores and in vitro cytotoxicity. It is proposed that the mechanism of action of the studied aminopyridines involves the disruption of signaling pathways and cancer cell cycle through the inhibition of cyclin-dependent kinases and several tyrosine kinases, namely Bcr-Abl kinase and KIT receptor kinase. The obtained results can guide further structural modifications of the studied compounds aimed at developing selective agents targeting proteins involved in cancer cell survival and proliferation.     

Effect of tomato genotypes with varying levels of susceptibility to Tetranychus evansi on performance and predation capacity of Phytoseiulus longipes

Tetranychus evansi Baker & Pritchard (Acari: Tetranychidae) is an invasive tomato pest in several African, American, Asian and European countries, with potential to reduce yield by up to 90%. Populations of the predaceous phytoseiid mite Phytoseiulus longipes Evans (Acari: Phytoseiidae) has been reported to have high potential for controlling T. evansi. However, tomato genotypes can potentially affect the performance of T. evansi and the predation ability of P. longipes. We evaluated the performance and predation capacity of P. longipes feeding on T. evansi nymphs on the two cultivated genotypes widely grown in Western Africa and a breeding genotype. The two commercial evaluated genotypes were Tounvi (susceptible, with few trichomes), TLCV15 (susceptible, with many trichomes), and the breeding genotype was SPJ-05–2018 (partially resistant with many glandular trichomes) selected from interspecific crossing TLCV15 and PI 13447 (highly resistant wild tomato genotype). We hypothesized that the susceptible genotype (with fewer trichomes) would be more favorable for P. longipes when compared to the susceptible or partially resistant genotypes (with a higher numbers of non-glandular or glandular trichomes). Intrinsic rate of increase (r) and predation potential (ω) of P. longipes were significantly reduced on SPJ-05–2018, possibly due to a negative effect of its glandular trichomes. Although the intrinsic rate of increase was higher on both susceptible genotypes (TLCV15 and Tounvi), predation potential was higher on TLCV15. Our results refuted the hypothesis that T. evansi-susceptible genotype with fewer trichomes would be more favorable to P. longipes.

     

Heterodimerization with vascular endothelial growth factor receptor-2 (VEGFR-2) is necessary for VEGFR-3 activity

VEGFR-3 is essential for vascular development and maintenance of lymphatic vessel's integrity. Little is known about its cooperative effect with other receptors of the same family. Contrary to VEGFR-2, stimulation of VEGFR-3 by VEGF-C and -D failed to enhance its phosphorylation either in HEK293T or in PAE cells. These ligands were unable to induce angiogenesis of PAEC expressing VEGFR-3 alone. In the presence of VEGFR-2, VEGF-C and -D induced heterodimerization of VEGFR-3 with VEGFR-2. This heterodimerization was associated with enhanced VEGFR-3 phosphorylation and subsequent cellular responses as evidenced by the formation of capillary-like structures in PAE cells and proliferation of primary human endothelial cells expressing both receptors. Taken together, these results show for the first time that VEGFR-3 needs to be associated to VEGFR-2 to induce ligand-dependent cellular responses.     

Eradication of Helicobacter pylori infection improves blood pressure values in patients affected by hypertension

Background. Arterial hypertension is a risk factor for atherosclerosis of whose pathogenesis is unknown. Growing evidence underscores the causative role of endothelial dysfunction. A possible association between Helicobacter pylori infection and cardiovascular and autoimmune disorders has been found. The release of cytotoxic substances either of bacterial origin or produced by the host may represent mediators of these systemic sequelae. The aim of our study was to determine the prevalence of H. pylori infection in hypertensive patients and the effects of H. pylori eradication on blood pressure and on digestive symptoms. Materials and Methods. Seventy‐two hypertensive patients (34 male and 38 female; mean age 53 ± 12 years) and 70 normotensive controls (35 male and 35 female; mean age 52 ± 10 years) were enrolled. All patients were subjected to a first ambulatory blood pressure monitoring (ABPM) at enrollment, a ¹³C urea breath test and a test for IgG‐CagA antibodies, and completed the validated dyspepsia questionnaire. H. pylori‐positive patients were treated with triple therapy (amoxicillin, clarithromycin and ranitidine bismute citrate) for 7 days. Control of eradication was assessed by ¹³C urea breath test, and all patients underwent a second ABPM 6 months after enrollment. Results. H. pylori infection was 55% in hypertensive patients, with 90% CagA positivity, and 50% in controls, with 60% CagA positivity. At the first ABPM, blood pressure values were similar in H. pylori‐positive and ‐negative individuals; positive patients showed a significant increase in pyrosis and epigastric pain compared to negative patients. H. pylori was eradicated in 80% of patients and in 85% of controls. At the second ABPM, we found a statistically significant decrease in 24‐hour mean blood pressure values when compared to the first ABPM only in the eradicated hypertensive group. Conclusions. Our study demonstrated a significant decrease in blood pressure values, in particular in diastolic blood pressure values, after H. pylori eradication in hypertensive patients. A high prevalence of CagA positivity was found. The association between cardiovascular disease and H. pylori infection seems pronounced only in CagA‐positive patients. The possible links between hypertensive disease and H. pylori infection may involve the activation of the cytokine cascade with the release of vasoactive substances from the primary site of infection, or molecular mimicry between the CagA antigens of H. pylori and some peptides expressed by endothelial cells and smooth muscle cells.     

Modulatory effects of garlic extracts on proliferation of T-lymphocytes in vitro stimulated with concanavalin A.

Different active components from the garlic (Allium sativum) possess immunomodulatory activity both in vitro and in vivo. However, mechanisms of their actions are not sufficiently elucidated. In this study we examined the effects of garlic aqueous extract (GAE) and garlic ethanolic extract (GEE), prepared from two different garlic powder samples, on proliferation of rat thymocytes and splenocytes in culture, stimulated with concanavalin A (Con A). It has been shown that the extracts from both samples significantly modulate lymphocyte proliferation, triggered by this potent T-cell mitogen, depending on the type and dilutions of extracts and concentrations of Con A. The extracts, alone, were not mitogenic for lymphocytes. Generally, higher concentrations of the extracts showed inhibitory effects, whereas lower concentrations significantly augmented proliferation of lymphocytes. The stimulatory effect of GAE was stronger using splenocytes and suboptimal concentrations of Con A as a consequence of increased interleukin 2 (IL-2) production as well as the expression of IL-2 receptor alpha (IL-2Ralpha). The relationship between these two phenomena was demonstrated using neutralizing anti-IL-2Ralpha monoclonal antibody. The inhibitory effect of GAE correlated with a decrease in IL-2 production, but was not followed by down-regulation of IL-2Ralpha expression. The addition of IL-2 almost completely abolished inhibition of lymphocyte proliferation in the presence of higher concentrations of GAE.     

Heat processing of soybean kernel and its effect on lysine availability and protein solubility

Soybean kernels of cultivars Bosa and ZPS 015 were used in the experiment. The contents of available lysine as well as water and salt soluble proteins, were analysed in fresh soybean kernels, soybean products made after the processes of dry extrusion, micronisation, microwave toasting and autoclaving. Utilizing a technological procedure of processing, kernels were exposed to temperatures from 57 to 150°C. The duration of exposure of the soybean kernels to the increased temperatures, ranged from 25-30 seconds in dry extrusion to 30 minutes in autoclaving. All treatments were subjected to different sources of heat, causing different thermodynamic processes to take place in kernels and change their chemical composition; i.e. nutritive quality. The content of water and salt soluble proteins decreased under the influence of higher temperatures in the course of all treatments of processing. The drop of solubility already was drastically effected by temperatures of 100°C in dry extrusion, while there was a gradual decrease in other treatments. The content of available lysine was determined by the modified Carpenter methods with DNFB. The processes of micronisation and microwave toasting showed the greatest effect on the reduction of lysine availability. Dry extrusion and autoclaving, performed within closed systems — in which the increased moisture content has a special effect — resulted in significantly smaller changes of the available lysine content.     

Appropriateness in allergic respiratory diseases health care in Italy: definitions and organizational aspects

In a historical period in which sustainability of the National Health Service is mandatory because of the international economical situation, the limited available resources at national level and the tendency of passing from a “population medicine” model towards the concept of “individualized medicine”, the debate on appropriateness of medical and surgical procedures is of central importance. The choosing wisely campaign, started in United States in 2012 and then spread all over the world, tries to summarize which are the most inappropriate procedures for each medical and surgical speciality; as far as allergic respiratory diseases, the most relevant Italian societies and the American Academy defined the allergological procedures with the highest probability of inappropriateness. In Italy, a recent decree of the Ministry of Health defined a list of more than 200 procedures that will be considered as inappropriate in certain conditions; many of these procedures concern allergology, including allergic respiratory diseases. In this commentary we discuss the above mentioned decree and the concept of appropriateness in the field of allergic respiratory diseases, trying to figure out some practical considerations based on the current health resources available in the field of allergology in Italy.     

pH control and the production of extracellular dextransucrase byLeuconostoc mesenteroides

The specific growth rate, the maximum specific dextransucrase production rate and the maximum dextransucrase yield during the dextransucrase fermentation byLeuconostoc mesenteroides were all unaffected by both the pH of the culture medium, maintained at 5.5 or 6.7, and the mode of pH control, by adding NaOH or K₂HPO₄.