PARTICIPATION OF Hi- AND H 3-RECEPTORS IN THE REGULATION OF GUINEA-PIG TRACHEAL TONE - INFLUENCE OF INDOMETHACIN

The tracheal tone is influenced by histaminergic receptors and by the epithelium derived relaxing factor (EpDRF) which contains metabolites of arachidonic acid. The aims of the present study were the following: 1) to investigate the role of Hi- and Нз-receptors in the tracheal tone regulation using as test substances histamine (H), the Hi-receptor antagonist mepyramine and the Нз-receptor agonist (R)a-methylhistamine [(R)a -MHA]; 2) to study the influence of the cyclooxygenase (COX) inhibitor indomethacin on the tracheal responsiveness to the examined substances. The experiments were carried out on isolated guinea-pig tracheal rings. Histamine at cumulative concentrations contracts the trachea. In the presence of mepyramine the concentration- response curves to H are shifted to the right that proves the concept of the Hi-receptor mediated tracheal contraction. In the presence of indomethacin the concentration-response curves to H are shifted to the left and the maximal contraction is significantly increased due to the inhibition of the COX pathway. (R)oc-MHA at concentrations up to lxlfH M leads to a slight tracheal contraction, which is probably Hi-receptor mediated as it is reduced in the presence of mepyramine. The ЗхКИ M concentration of (R)a-MHA relaxes the trachea probably due to its Нз-receptor agonistic activity. In the presence of indomethacin this relaxation is turned to a further contraction. After tracheal precontraction by H, (R)a-MHA concentration dependently relaxes the trachea. This spasmolytic effect is insignificantly influenced by mepyramine and is almost completely abolished in the presence of indomethacin, which shows that it is probably due to an increased production of metabolites of arachidonic acid

Study of Natural Aronia Melanocarpa Fruit Juice for Antibacterial and Antiviral Activity

Natural Aronia melanocarpa fruit juice (AMFJ) is rich in polyphenols most of which are anthocyanins. These compounds and other natural plant products are recently evaluated for their anti-infectious activity. The aim of the present study was to investigate the antibacterial and antiviral activity of AMFJ. AMFJ bacteriostatic activity on referent strains of S. aureus ATCC 25923, E. coli ATCC 25922 and P. aeruginosa ATCC 27853 was assessed by counting the number of colonies after 24h incubation at 37°C using the microbial number method. AMFJ was not bacteriostatic for P. aeruginosa. The microbial number for E. coli was 0 ,3 6xl02 CFU/ml AMFJ and for N. aureus 0,87x10s CFU/ml AMFJ. Gram-positive bacteria should mainly be used as a test for further investigation of the bacteriostatic activity of AMFJ. AMFJ antiviral activity directed to the reproduction in ovo of influenza virus type A (H3N2) was investigated. AMFJ inhibited the reproduction of influenza virus in its initial stages, most probably, due to the formation of complex compounds between the virion, on one hand, and the polyphenols, on the other hand, which influenced the adsorption of the influenza virus on the cell surface

Influence of Fruit Juice From Aronia Melanocarpa on the Process of Lipid Peroxidation in a Model of Carbon Tetrachloride-Induced Hepatotoxicity in Rats

The fruit juice from Aronia melanocarpa (FJAM) is rich in anthocyanins. We studied the effect of FJAM on the process of lipid peroxidation in a model of carbon tetrachloride (CCI4)-induced hepatotoxicity in rats. Malondialdehyde (MDA) levels were measured in plasma and liver homogenate. CCU induced a significant elevation of MDA levels in the plasma (p<0,05) and in the homogenate (p<0,01) in comparison with distilled water-treated controls. FJAM applied alone did not significantly influence on the MDA levels. The pretreatment of the rats with FJAM before their treatment with CCI4 lead dose-dependently to MDA levels in the plasma and homogenate which did not differ in most animal groups from the controls and were significantly lower from those of the CCI4-treated rats

PHARMACOGENETIC STUDY OF THE ACETYLATION PHENOTYPE IN A BULGARIAN POPULATION

N-acetyltransferase, an enzyme involved in the metabolic inactivation of drugs like isoniazide, some sulfonamides and others is well-known to he under polymorphic genetic control. The acetylation phenotype of the patients may serve as an important guide in foretelling the therapeutic efficacy or tolerahility of a particular drug. In the present study we investigated the distribution of the acetylaiion phenotypes in a group of 100 healthy volunteers of both sexes using sulfadimidine as a substrate. The distribution was found to follow a bimodal pattern, as aspected, with a slight predominance of the "slow" acetylators - in 58 % of the cases, a finding similar to literature data from neighbouring and other European countries. In the men's group the distribution was approximately the same as that in the whole group whilst in the women's one the "rapid" inactivators prevailed. This work represents the first modest attempt in Bulgaria for phenotyping the population according to the individual acetylaiion status

Effects of Aronia melanocarpa fruit juice on exploratory behaviour and locomotor activity in rats

The main bioactive substances in Aronia melanocarpa fruit juice (AMFJ) are polyphenols (flavonoids, procyanidins, and phenolic acids). A great number of polyphenols are able to traverse the blood-brain barrier. In recent years more attention is drawn to the ability of these substances to influence central nervous system functions. The aim of the present study was to investigate the effects of AMFJ on exploratory behaviour and locomotor activity in male Wistar rats. AMFJ was administered orally for 7, 14, 21, and 30 days at three increasing doses (2.5, 5, and 10 ml kg−1). The changes in exploratory behaviour and locomotor activity were recorded in an Opto Varimex apparatus. It was found that the low doses of AMFJ (2.5 and 5 ml kg−1) for all treatment periods did not significantly affect exploratory behaviour and locomotor activity of rats compared to the saline-treated controls. AMFJ at the highest dose of 10 ml kg−1 had no significant effect on exploration and locomotion for the treatment periods of 7 and 14 days, while for the periods of 21 and 30 days it significantly decreased the number of horizontal and vertical movements, which might be the result of a sedative effect. At all the doses and testing periods, AMFJ did not disturb the progressive decrease in motor behaviour, suggesting habituation

The astrometric Gaia-FUN-SSO observation campaign of 99 942 Apophis

Astrometric observations performed by the Gaia Follow-Up Network for Solar System Objects (Gaia-FUN-SSO) play a key role in ensuring that moving objects first detected by ESA's Gaia mission remain recoverable after their discovery. An observation campaign on the potentially hazardous asteroid (99 942) Apophis was conducted during the asteroid's latest period of visibility, from 12/21/2012 to 5/2/2013, to test the coordination and evaluate the overall performance of the Gaia-FUN-SSO . The 2732 high quality astrometric observations acquired during the Gaia-FUN-SSO campaign were reduced with the Platform for Reduction of Astronomical Images Automatically (PRAIA), using the USNO CCD Astrograph Catalogue 4 (UCAC4) as a reference. The astrometric reduction process and the precision of the newly obtained measurements are discussed. We compare the residuals of astrometric observations that we obtained using this reduction process to data sets that were individually reduced by observers and accepted by the Minor Planet Center. We obtained 2103 previously unpublished astrometric positions and provide these to the scientific community. Using these data we show that our reduction of this astrometric campaign with a reliable stellar catalog substantially improves the quality of the astrometric results. We present evidence that the new data will help to reduce the orbit uncertainty of Apophis during its close approach in 2029. We show that uncertainties due to geolocations of observing stations, as well as rounding of astrometric data can introduce an unnecessary degradation in the quality of the resulting astrometric positions. Finally, we discuss the impact of our campaign reduction on the recovery process of newly discovered asteroids.Comment: Accepted for publication in A&

Chemotherapy-induced ileal crypt apoptosis and the ileal microbiome shape immunosurveillance and prognosis of proximal colon cancer

The prognosis of colon cancer (CC) is dictated by tumor-infiltrating lymphocytes, including follicular helper T (TFH) cells and the efficacy of chemotherapy-induced immune responses. It remains unclear whether gut microbes contribute to the elicitation of TFH cell-driven responses. Here, we show that the ileal microbiota dictates tolerogenic versus immunogenic cell death of ileal intestinal epithelial cells (IECs) and the accumulation of TFH cells in patients with CC and mice. Suppression of IEC apoptosis led to compromised chemotherapy-induced immunosurveillance against CC in mice. Protective immune responses against CC were associated with residence of Bacteroides fragilis and Erysipelotrichaceae in the ileum. In the presence of these commensals, apoptotic ileal IECs elicited PD-1+ TFH cells in an interleukin-1R1- and interleukin-12-dependent manner. The ileal microbiome governed the efficacy of chemotherapy and PD-1 blockade in CC independently of microsatellite instability. These findings demonstrate that immunogenic ileal apoptosis contributes to the prognosis of chemotherapy-treated CC

Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells

Neuropilin-1 (NRP-1) is a novel co-receptor for vascular endothelial growth factor (VEGF). Neuropilin-1 is expressed in pancreatic cancer, but not in nonmalignant pancreatic tissue. We hypothesised that NRP-1 expression by pancreatic cancer cells contributes to the malignant phenotype. To determine the role of NRP-1 in pancreatic cancer, NRP-1 was stably transfected into the human pancreatic cancer cell line FG. Signal transduction was assessed by Western blot analysis. Susceptibility to anoikis (detachment induced apoptosis) was evaluated by colony formation after growth in suspension. Chemosensitivity to gemcitabine or 5-fluorouracil (5-FU) was assessed by MTT assay in pancreatic cancer cells following NRP-1 overexpression or siRNA-induced downregulation of NRP-1. Differential expression of apoptosis-related genes was determined by gene array and further evaluated by Western blot analysis. Neuropilin-1 overexpression increased constitutive mitogen activated protein kinase (MAPK) signalling, possibly via an autocrine loop. Neuropilin-1 overexpression in FG cells enhanced anoikis resistance and increased survival of cells by >30% after exposure to clinically relevant levels of gemcitabine and 5-FU. In contrast, downregulation of NRP-1 expression in Panc-1 cells markedly increased chemosensitivity, inducing >50% more cell death at clinically relevant concentrations of gemcitabine. Neuropilin-1 overexpression also increased expression of the antiapoptotic regulator, MCL-1. Neuropilin-1 overexpression in pancreatic cancer cell lines is associated with (a) increased constitutive MAPK signalling, (b) inhibition of anoikis, and (c) chemoresistance. Targeting NRP-1 in pancreatic cancer cells may downregulate survival signalling pathways and increase sensitivity to chemotherapy