1,8-Cineol inhibits nuclear translocation of NF-κB p65 and NF-κB-dependent transcriptional activity

Natural plant-derived products are commonly applied to treat a broad range of human diseases, including cancer as well as chronic and acute airway inflammation. In this regard, the monoterpene oxide 1,8-cineol, the active ingredient of the clinically approved drug Soledum®, is well-established for the therapy of airway diseases, such as chronic sinusitis and bronchitis, chronic obstructive pulmonary disease and bronchial asthma. Although clinical trials underline the beneficial effects of 1,8-cineol in treating inflammatory diseases, the molecular mode of action still remains unclear. Here, we demonstrate for the first time a 1,8-cineol-depending reduction of NF-κB-activity in human cell lines U373 and HeLa upon stimulation using lipopolysaccharides (LPS). Immunocytochemistry further revealed a reduced nuclear translocation of NF-κB p65, while qPCR and western blot analyses showed strongly attenuated expression of NF-κB target genes. Treatment with 1,8-cineol further led to increased protein levels of IκBα in an IKK-independent matter, while FRET-analyses showed restoring of LPS-associated loss of interaction between NF-κB p65 and IκBα. We likewise observed reduced amounts of phosphorylated c-Jun N-terminal kinase 1/2 protein in U373 cells after exposure to 1,8-cineol. In addition, 1,8-cineol led to decreased amount of nuclear NF-κB p65 and reduction of its target gene IκBα at protein level in human peripheral blood mononuclear cells. Our findings suggest a novel mode of action of 1,8-cineol through inhibition of nuclear NF-κB p65 translocation via IκBα resulting in decreased levels of proinflammatory NF-κB target genes and may therefore broaden the field of clinical application of this natural drug for treating inflammatory diseases.

The 'direct costs' of livestock disease: The development of a system of models for the analysis of 30 endemic livestock diseases in Great Britain

The 'direct costs' attributable to 30 different endemic diseases of farm animals in Great Britain are estimated using a standardised method to construct a simple model for each disease that includes consideration of disease prevention and treatment costs. The models so far developed provide a basis for further analyses including cost-benefit analyses for the economic assessment of disease control options. The approach used reflects the inherent livestock disease information constraints, which limit the application of other economic analytical methods. It is a practical and transparent approach that is relatively easily communicated to veterinary scientists and policy makers. The next step is to develop the approach by incorporating wider economic considerations into the analyses in a way that will demonstrate to policy makers and others the importance of an economic perspective to livestock disease issues.

Updated estimates of the costs associated with thirty four endemic livestock diseases in Great Britain: A note

This Note outlines the further development of a system of models for the estimation of the costs of livestock diseases first presented by Bennett (2003). The models have been developed to provide updated and improved estimates of the costs associated with 34 endemic diseases of livestock in Great Britain, using border prices and including assessments of the impact of diseases on human health and animal welfare. Results show that, of the diseases studied, mastitis has the highest costs for cattle diseases, enzootic abortion for sheep diseases, swine influenza for pig diseases and salmonellosis for poultry diseases.

The survival advantage of milk and dairy consumption: An overview of evidence from cohort studies of vascular diseases, diabetes and cancer

Objectives: To conduct it detailed evaluation, with meta-analyses, of the published evidence on milk and dairy consumption and the incidence of vascular diseases and diabetes. Also to summarise the evidence on milk and dairy consumption and cancer reported by the World Cancer Research Fund and then to consider the relevance of milk and dairy consumption to survival in the UK, a typical Western community. Finally, published evidence on relationships with whole milk and fat-reduced milks was examined. Methods: Prospective cohort studies of vascular disease and diabetes with baseline data on milk or dairy consumption and a relevant disease outcome were identified by searching MEDLINE, and reference lists in the relevant published reports. Meta-analyses of relationships in these reports were conducted. The likely effect of milk and dairy consumption on survival was then considered, taking into account the results of published overviews of relationships of these foods with cancer. Results: From meta-analysis of 15 studies the relative risk of stroke and/or heart disease in subjects with high milk or dairy consumption was 0.84 (95% CI 0.76, 0,93) and 0.79 (0.75, 0.82) respectively, relative to the risk in those with low consumption. Four studies reported incident diabetes as an outcome, and the relative risk in the Subjects with the highest intake of milk or diary foods was 0.92 (0.86, 0.97). Conclusions: Set against the proportion of total deaths attributable to the life-threatening diseases in the UK, vascular disease, diabetes and cancer, the results of meta-analyses provide evidence of an overall survival advantage from the consumption of milk and dairy foods.

Influence of foliar diseases and their control by fungicides on grain yield and quality in wheat

Twenty-eight field experiments on sandy-loam soils in the UK (1982-2003) are reviewed by relating the extension of the green area duration of the flag leaf (GLADF) by fungicides to effects on yield and quality of winter wheat. Over all experiments mean grain yield = 8.85t ha(-1) at 85% DM. With regards quality, mean values were: thousand grain weight (TGW) = 44.5 g; specific weight (SWT) = 76.9 kg hl(-1); crude protein concentration (CP (N x 5.7)) = 12.5 % DM; Hagberg falling number (HFN) = 285 s; and sodium dodecyl sulphate (SDS)-sedimentation volume = 69ml. For each day (d) that fungicides increased GLADF there were associated average increases in yield (0.144 1 ha(-1) d(-1), se 0.0049, df = 333), TGW (0.56 gd(-1), se = 0.017) and SWT (0.22 kg hl(-1) d(-1), se 0.011). Some curvature was evident in all these relationships. When GLADF was delayed beyond 700 degrees Cd after anthesis, as was possible in cool wet seasons, responses were curtailed, or less reliable. Despite this apparent terminal sink limitation, fungicide effects on sink size, eg endosperm cell numbers or maximum water mass per grain, were not prerequisites for large effects on grain yield, TGW or SWT. Fungicide effects on CP were variable. Although the average response of CP was negative (-0.029%DM/d; se = 0.00338), this depended on cultivar and disease controlled. Controlling biotrophs such as rusts, (Puccinia spp.) tended to increase CP, whereas controlling a more necrotrophic pathogen (Septoria tritici) usually reducedCP. Irrespective of pathogen controlled, delaying senescence of the flag leaf was associated with increased nitrogen yields in the grain (averaging 2.24 kg N ha-1 d(-1), se = 0.0848) due to both increased N uptake into the above ground crop, and also more efficient remobilisation of N from leaf laminas. When sulphur availability appeared to be adequate, fungicide x cultivar interactions were similar on S as for CP, although N:S ratios tended to decline (i.e. improve for bread making) when S. tritici was controlled. On average, SDS-sedimentation volume declined (-0. 18 ml/d, se = 0.027) with increased GLADF, broadly commensurate with the average effect on CP. Hagberg falling number decreased as fungicide increased GLADF (-2.73 s/d, se = 0.178), indicating an increase in alpha-amylase activity.

Mutations in H5N1 influenza virus hemagglutinin that confer binding to human tracheal airway epithelium

The emergence in 2009 of a swine-origin H1N1 influenza virus as the first pandemic of the 21st Century is a timely reminder of the international public health impact of influenza viruses, even those associated with mild disease. The widespread distribution of highly pathogenic H5N1 influenza virus in the avian population has spawned concern that it may give rise to a human influenza pandemic. The mortality rate associated with occasional human infection by H5N1 virus approximates 60%, suggesting that an H5N1 pandemic would be devastating to global health and economy. To date, the H5N1 virus has not acquired the propensity to transmit efficiently between humans. The reasons behind this are unclear, especially given the high mutation rate associated with influenza virus replication. Here we used a panel of recombinant H5 hemagglutinin (HA) variants to demonstrate the potential for H5 HA to bind human airway epithelium, the predominant target tissue for influenza virus infection and spread. While parental H5 HA exhibited limited binding to human tracheal epithelium, introduction of selected mutations converted the binding profile to that of a current human influenza strain HA. Strikingly, these amino-acid changes required multiple simultaneous mutations in the genomes of naturally occurring H5 isolates. Moreover, H5 HAs bearing intermediate sequences failed to bind airway tissues and likely represent mutations that are an evolutionary "dead end." We conclude that, although genetic changes that adapt H5 to human airways can be demonstrated, they may not readily arise during natural virus replication. This genetic barrier limits the likelihood that current H5 viruses will originate a human pandemic.

Infection of human airway epithelium by human and avian strains of influenza a virus

We describe the characterization of influenza A virus infection of an established in vitro model of human pseudostratified mucociliary airway epithelium (HAE). Sialic acid receptors for both human and avian viruses, alpha-2,6- and alpha-2,3-linked sialic acids, respectively, were detected on the HAE cell surface, and their distribution accurately reflected that in human tracheobronchial tissue. Nonciliated cells present a higher proportion of alpha-2,6-linked sialic acid, while ciliated cells possess both sialic acid linkages. Although we found that human influenza viruses infected both ciliated and nonciliated cell types in the first round of infection, recent human H3N2 viruses infected a higher proportion of nonciliated cells in HAE than a 1968 pandemic-era human virus, which infected proportionally more ciliated cells. In contrast, avian influenza viruses exclusively infected ciliated cells. Although a broad-range neuraminidase abolished infection of HAE by human parainfluenza virus type 3, this treatment did not significantly affect infection by influenza viruses. All human viruses replicated efficiently in HAE, leading to accumulation of nascent virus released from the apical surface between 6 and 24 h postinfection with a low multiplicity of infection. Avian influenza A viruses also infected HAE, but spread was limited compared to that of human viruses. The nonciliated cell tropism of recent human H3N2 viruses reflects a preference for the sialic acid linkages displayed on these cell types and suggests a drift in the receptor binding phenotype of the H3 hemagglutinin protein as it evolves in humans away from its avian virus precursor.

The adrenal secretory serine protease AsP is a short secretory isoform of the transmembrane airway trypsin-like protease

To further elucidate the role of proteases capable of cleaving N-terminal proopiomelanocortin (N-POMC)-derived peptides, we have cloned two cDNAs encoding isoforms of the airway trypsin-like protease (AT) from mouse (MAT) and rat ( RAT), respectively. The open reading frames comprise 417 amino acids (aa) and 279 aa. The mouse AT gene was located at chromosome 5E1 and contains 10 exons. The longer isoform, which we designated MAT1 and RAT1, has a simple type II transmembrane protein structure, consisting of a short cytoplasmic domain, a transmembrane domain, a SEA (63-kDa sea urchin sperm protein, enteropeptidase, agrin) module, and a serine protease domain. The human homolog of MAT1 and RAT1 is the human AT ( HAT). The shorter isoform, designated MAT2 and RAT2, which contains an alternative N terminus, was formerly described in the rat as adrenal secretory serine protease (AsP) and has been shown to be involved in the processing of N-POMC-derived peptides. In contrast to the long isoform, neither MAT2 and RAT2 ( AsP) contain a transmembrane domain nor a SEA domain but an N-terminal signal peptide to direct the enzyme to the secretory pathway. The C terminus, covering the catalytic triad, is identical in both isoforms. Immunohistochemically, MAT/RAT was predominantly expressed in tissues of the upper gastrointestinal and the respiratory tract - but also in the adrenal gland. Moreover, isoform-specific RT-PCR and quantitative PCR analysis revealed a complex expression pattern of the two isoforms with differences between mice and rats. These findings indicate a multifunctional role of these proteases beyond adrenal proliferation.

Effects of straw and silicon soil amendments on some foliar and stem-base diseases in pot-grown winter wheat

Four foliar and two stem-base pathogens were inoculated onto wheat plants grown in different substrates in pot experiments. Soils from four different UK locations were each treated in three ways: (i) straw incorporated in the field at 10 t ha−1 several months previously; (ii) silicon fertilization at 100 mg L−1 during the experiment; and (iii) no amendments. A sand and vermiculite mix was used with and without silicon amendment. The silicon treatment increased plant silica concentrations in all experiments, but incorporating straw was not associated with raised plant silica concentrations. Blumeria graminis and Puccinia recondita were inoculated by shaking infected plants over the test plants, followed by suitable humid periods. The silicon treatment reduced powdery mildew (B. graminis) substantially in sand and vermiculite and in two of the soils, but there were no effects on the slight infection by brown rust (P. recondita). Phaeosphaeria nodorum and Mycosphaerella graminicola were inoculated as conidial suspensions. Leaf spot caused by P. nodorum was reduced in silicon-amended sand and vermiculite; soil was not tested. Symptoms of septoria leaf blotch caused by M. graminicola were reduced by silicon amendment in a severely infected sand and vermiculite experiment but not in soil or a slightly infected sand and vermiculite experiment. Oculimacula yallundae (eyespot) and Fusarium culmorum (brown foot rot) were inoculated as agar plugs on the stem base. Severity of O. yallundae was reduced by silicon amendment of two of the soils but not sand and vermiculite; brown foot rot symptoms caused by F. culmorum were unaffected by silicon amendment. The straw treatment reduced severity of powdery mildew but did not detectably affect the other pathogens. Both straw and silicon treatments appeared to increase plant resistance to all diseases only under high disease pressure.