PPARγ ligands, 15-deoxy-Δ12,14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth muscle proliferation through different mechanisms

1. The influence of two peroxisome proliferator-activated receptor γ (PPARγ) ligands, a thiazolidinedione, rosiglitazone (RG) and the prostaglandin D2 metabolite 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) on the proliferation of human cultured airway smooth muscle (HASM) was examined.

2. The increases in HASM cell number in response to basic fibroblast growth factor (bFGF, 300 pm) or thrombin (0.3 U ml−1) were significantly inhibited by either RG (1–10 μm) or 15d-PGJ2 (1–10 μm). The effects of RG, but not 15d-PGJ2, were reversed by the selective PPARγ antagonist GW9662 (1 μm).

3. Neither RG nor 15d-PGJ2 (10 μm) decreased cell viability, or induced apoptosis, suggesting that the regulation of cell number was due to inhibition of proliferation, rather than increased cell death.

4. Flow-cytometric analysis of HASM cell cycle distribution 24 h after bFGF addition showed that RG prevented the progression of cells from G1 to S phase. In contrast, 15d-PGJ2 caused an increase in the proportion of cells in S phase, and a decrease in G2/M, compared to bFGF alone.

5. Neither RG nor 15d-PGJ2 inhibited ERK phosphorylation measured 6 h post mitogen addition. The bFGF-mediated increase in cyclin D1 protein levels after 8 h was reduced in the presence of 15d-PGJ2, but not RG.

6. Although both RG and 15d-PGJ2 can inhibit proliferation of HASM irrespective of the mitogen used, only the antiproliferative effects of RG appear to be PPARγ-dependent. The different antimitogenic mechanisms of 15d-PGJ2 and synthetic ligands for PPARγ may be exploited to optimise the potential for these compounds to inhibit airway remodelling in asthma.

Mechanisms involved in the therapeutic effects of soybean (glycine max)

Soybeans contain nutritional and medicinal properties. It is a rich source of quality proteins, phytosterols, fibers, and other biologically active compounds, notably daidzein and genistein. Soybeans provide health benefits due to their functional ingredients such as proteins, polysaccharides, and isoflavones. These functional ingredients play a vital role in the reduction of different types of cancer, cardiovascular diseases, postmenopausal problems, diabetes, and some neurodegenerative disorders. This review primarily envisages the different mechanisms involved in the therapeutic effects of soybean components as well as their contribution toward the reduction of different diseases.

Recrystallization in 304 austenitic stainless steel

A 304 austenitic stainless steel was deformed using hot torsion to study the evolution of dynamic recrystallization (DRX). The initial nucleation of dynamically recrystallization occurred by the bulging of pre-existing high angle grain boundaries at a strain much lower than the peak strain. At the
peak stress, only a low fraction of the prior grain boundaries were covered with new DRX grains. Beyond the peak stress, new DRX grains formed layers near the initial DRX and a necklace structure was developed. Several different mechanisms appeared to be operative in the formation of new high angle boundaries and grains. The recrystallization behaviour after deformation showed a classic transition from strain dependent to strain independent softening. This occurred at a strain beyond the
peak, where the fraction of dynamic recrystallization was only 50%.

Derivative actions as a mechanism for the protection of minority shareholders in China: a result of convergence or divergence

The protection of minority shareholders has become one of the key features of company law reform in many countries in recent years. Various mechanisms have been created to achieve this objective. Australia has introduced the statutory derivative action procedure mainly based on models drawn from Canada and New Zealand; this provision was inserted into the Corporations Act in March 2000. China has also adopted a similar mechanism – known as the shareholder representative action; this scheme was based upon China’s understanding of statutory derivative actions in Western countries. China’s derivative action mechanism is reflected in amendments to the 2005 PRC Company Law and 2005 Securities Law that both were passed on 27 October 2005 and came into effective on 1 January 2006. The development of statutory derivative actions in different countries demonstrates the interaction between forces of convergence and divergence in company law reforms. This article reviews different mechanisms adopted in the Chinese law for the protection of minority shareholders. It especially focuses on an analysis of the nature of the shareholder representative action and the procedures for its utilisation in China – the equivalent to Western countries’ derivative actions. In comparison with statutory derivative actions in Australia, this article argues that the concept of the shareholder representative action in China rests upon a misunderstanding of Western derivative actions; this has involved a compromise between the dire need to protect shareholders and the ambiguities of a weak court system. As a consequence, China’s reforms in this area are largely a tentative gesture and are therefore unlikely to be very effective.

Texture changes during uniaxial compression of Mg-3AI-1Zn

The mechanical anisotropy of wrought Mg alloys is very high. For example the yield stress of extruded Mg-3Al-1Zn tested in tension can be as high as twice that obtained in compression [1]. To solve the problems this creates for product design it is necessary to understand the sensitivity of texture to processing parameters. Uniaxial compression tests at different temperatures were performed on cylindrical samples of an extruded Mg-3Al-1Zn bar. The texture
during this deformation changes from a situation where all crystal c-axes are nearly perpendicular to the sample axis to one where the c-axes are all nearly parallel to this axis. Compression was stopped at different strains to examine the rate of this texture change. Textures were examined using EBSD measurements. It was found that different mechanisms operate depending on the temperature of deformation and that a variety of textures can be created. Also it was seen that an annealing treatment performed after compression has an influence on the texture. Afterwards the samples were subjected to another uniaxial compression test to examine the influence of texture on room temperature properties.

Copper is taken up efficiently from albumin and α2-macroglobulin by cultured human cells by more than one mechanism

Ionic copper entering blood plasma binds tightly to albumin and the macroglobulin transcuprein. It then goes primarily to the liver and kidney except in lactation, where a large portion goes directly to the mammary gland. Little is known about how this copper is taken up from these plasma proteins. To examine this, the kinetics of uptake from purified human  albumin and α2-macroglobulin, and the effects of inhibitors, were measured using human hepatic (HepG2) and mammary epithelial (PMC42) cell lines. At physiological concentrations (3–6 µM), both cell types took up copper from these proteins independently and at rates similar to each other and to those for Cu-dihistidine or Cu-nitrilotriacetate (NTA). Uptakes from   α2-macroglobulin indicated a single saturable system in each cell type, but with different kinetics, and 65–80% inhibition by Ag(I) in HepG2 cells but not PMC42 cells. Uptake kinetics for Cu-albumin were more complex and also differed with cell type (as was the case for Cu-histidine and NTA), and there was little or no inhibition by Ag(I). High Fe(II) concentrations (100–500 µM) inhibited copper uptake from albumin by 20–30% in both cell types and that from {alpha}2-macroglobulin by 0–30%, and there was no inhibition of the latter by Mn(II) or Zn(II). We conclude that the proteins mainly responsible for the plasma-exchangeable copper pool deliver the metal to mammalian cells efficiently and by several different mechanisms.α2-Macroglobulin delivers it primarily to copper transporter 1 in hepatic cells but not mammary epithelial cells, and additional as-yet-unidentified copper transporters or systems for uptake from these proteins remain to be identified.

Amylase and glucosidase enzyme inhibitory activity of ginger (Zingiber officinale Roscoe) an in vitro study

The prevalence of type 2 diabetes has reached to an epidemic proportion in Sri Lanka. The need for achieving better control of blood glucose level has been evident in diabetes management. However it is not easy to achieve this goal in a large proportion of patients. This is partly due to limitations of currently available pharmacological agents which stimulate research on novel anti-diabetic agents with different mechanisms. Digestive enzymes have been targeted as potential avenues for modulation of blood glucose concentration through inhibition of the enzymatic breakdown of complex carbohydrates to meal derived glucose absorption. Acarbose is a widely used oral anti-diabetic drug which inhibits the α-glucosidase, enzyme responsible for breaking down of disaccharides and polysaccharides into glucose. Many herbal extracts have been found to posses similar inhibitory effects. Ginger (Zingiber officinale Roscoe) has developed a reputation in treatment of several diseases. In vitro enzymic inhibitory effect of ginger was investigated in this study. Enzymes α -amylase and α -glucosidase treated with either Acarbose or ginger extract were allowed to react with cooked rice and percentages of glucose content were measured. The glucosidase and amylase activities on the rice were inhibited by addition of ginger cause significant reduction in glucose percentages (36.86± 1.05 to 26.87± 2.17, P<0.05 and 49.04±0.65 to 35.35±2.22, P<0.05) which showed comparable results with Acarbose on glucosidase activity (36.86± 1.05 to, 27.8±1.32 P<0.05). Results of the study indicates ginger as a potential plant based amylase and glucosidase inhibitor in carbohydrate digestion but usage in glycaemic control in human has to be investigated further.

Alterations in renal and myocardial adrenoceptors associated with ethynyloestradiol- and levonorgestrel-induced hypertension in the rat

Hypertension is one of many side effects of oral contraceptive use in a small percentage of women. Although the underlying pathology has yet to be fully resolved, alterations in the renin-angiotensin-aldosterone axis, sympathetic nervous system/ renal and cardiac function have been implicated. In the thesis to be presented, the possible involvement of alterations in renal and myocardial adrenoceptor characteristics in the pathogenesis of steroid contraceptive-induced hypertension in rats was examined by radioligand binding techniques. In Chapter 2, a rat model of OC hypertension is described. Chronic low-dose administration of ethynyloestradiol (EE2), levonorgestrel (NG) or a combination of both steroids (EE2/NG) to female Sprague-Dawley rats was shown to significantly increase systolic blood pressure (SBP). Renal and cardiac hypertrophy developed in association with EE2-, EE2/NG- but not NG-induced hypertension. Moreover, whereas administration of NG alone attenuated body weight gain, combined EE2/NG administration increased body weight gain from the second week of treatment onwards. Based on the above observations, it is proposed that EE2 and NG induce hypertension in rats via different mechanisms. Although SBP was elevated to a similar maximum in all steroid-treated groups (+ 20 mmHg compared to controls), only with EE2 administration did SBP remain elevated for the duration of the 17 week treatment regimen. NG may therefore have a protective effect on blood pressure with long-term combined steroid contraceptive treatment. In Chapter 4, renal adrenoceptors were characterized using radioactively labelled adrenocephor antagonists. Under appropriate conditions, binding of [3H]-prazosin and [3H]-rauwolscine to membrane preparations of whole rat kidney displayed the kinetics, saturability and specificity of α1- and α2 -adrenoceptors respectively, which were present in a ratio 3:1. In contrast, [3H]-dihydroergocryptine ([3H]-DHE) apparently bound to both α1 and α2-adrenoceptors. Binding sites identified by [125I] –iodocyanopindolol (ICYP) had the recognition characteristics of β-adrenoceptors. In drug competition studies using the subtype-selective antagonists practolol (β1) and ICI 118,551 (β2)/ the ratio of β1- to β2 -adrenoceptors was found to be approximately 2:1. Subsequently, renal adrenoceptors were investigated at various stages during the development of hypertension with the different steroid contraceptive treatments (Chapters 5 and 6). Preliminary binding studies with [3H]-DHE and [3H]-prazosin suggested that the number of renal α2 - but not α1-adrenoceptors was reduced in rats with established EE2-induced hypertension (17 weeks treatment). This was subsequently confirmed using [3H]-rauwolscine, which in addition showed that the reduction in renal α2 -adrenoceptor number occurred during the developmental stage of EE2/NG~induced hypertension (6 weeks treatment) and established EE2-induced hypertension (12 weeks treatment). NG induced hypertension was unassociated with changes in renal α1- and α2-adrenoceptor characteristics. Renal β-adrenoceptor affinity was reduced in established EE2-, but not NG- or EE2/NG- induced hypertension. Moreover, the β-adrenoceptor agonist (-)-isoprenaline bound to renal β-adrenoceptors with reduced affinity following EE2 administration. Several endogenous and synthetic steroids were found to be ineffective inhibitors of [3H] –prazosin, [3H] –rauwolscine and ICYP binding excluding a direct interaction of these steroids with renal α1-, α2- and β -adrenoceptors. In Chapter 7, myocardial adrenoceptors were characterized and investigated in steroid-treated rats. In membrane preparations of whole myocardium, [3H]-prazosin binding was characteristically to α1- adrenoceptors, whereas there was a notable absence of [3H]-rauwolscine binding. Using ICYP, β-adrenoceptors were also detected, the ratio of β1- to β2~adrenoceptors being 3:1. Steroid contraceptive-induced hypertension was not associated with myocardial α1-adrenoceptor changes. Similarly, myocardial β-adrenoceptors were unchanged in established EE2-, NG- and EE2/NG-induced hypertension (12 weeks treatment). The affinity of (-)-isoprenaline for myocardial β-adrenoceptors was unaffected by EE2 aditiinistration. These studies suggest that established EE2- but not NG-induced hypertension in rats is associated with selective alterations in renal α2- and (β-adrenoceptors. These adrenoceptor changes may help to maintain elevated blood pressure by affecting the control of renal function by the sympathetic nervous system, catecholamines and several hormones which affect renin release and the transport of fluid and electrolytes in the nephron.

Viral RNA silencing suppressors (RSS) : novel strategy of viruses to ablate the host RNA interference (RNAi) defense system

Pathogenic viruses have developed a molecular defense arsenal for their survival by counteracting the host anti-viral system known as RNA interference (RNAi). Cellular RNAi, in addition to regulating gene expression through microRNAs, also serves as a barrier against invasive foreign nucleic acids. RNAi is conserved across the biological species, including plants, animals and invertebrates. Viruses in turn, have evolved mechanisms that can counteract this anti-viral defense of the host. Recent studies of mammalian viruses exhibiting RNA silencing suppressor (RSS) activity have further advanced our understanding of RNAi in terms of host–virus interactions. Viral proteins and non-coding viral RNAs can inhibit the RNAi (miRNA/siRNA) pathway through different mechanisms. Mammalian viruses having dsRNA-binding regions and GW/WG motifs appear to have a high chance of conferring RSS activity. Although, RSSs of plant and invertebrate viruses have been well characterized, mammalian viral RSSs still need in-depth investigations to present the concrete evidences supporting their RNAi ablation characteristics. The information presented in this review together with any perspective research should help to predict and identify the RSS activity-endowed new viral proteins that could be the potential targets for designing novel anti-viral therapeutics.

Security framework for mobile agents-based applications

Mobile agents have been proposed for key applications such as forensics analysis, intrusion detection, e-commerce, and resource management. Yet, they are vulnerable to various security threats by malicious hosts or intruders. Conversely, genuine platforms may run malicious agents. It is essential to establish a truly secure framework for mobile agents to gain trust of clients in the system. Failure to accomplish a trustworthy secured framework for Mobile Agent System (MAS) will limit their deployment into the key applications. This chapter presents a comprehensive taxonomy of various security threats to Mobile Agent System and the existing implemented security mechanisms. Different mechanisms are discussed, and the related security deficiencies are highlighted. The various security properties of the agent and the agent platform are described. The chapter also introduces the properties, advantages, and roles of agents in various applications. It describes the infrastructure of the system and discusses several mobile agent frameworks and the accomplished security level.

MicroRNA pathways : an emerging role in identification of therapeutic strategies

For years researchers have exerted every effort to improve the influential roles of microRNA (miRNA) in regulating genes that direct mammalian cell development and function. In spite of numerous advancements, many facets of miRNA generation remain unresolved due to the perplexing regulatory networks. The biogenesis of miRNA, eminently endures as a mystery as no universal pathway defines or explicates the variegation in the rise of miRNAs. Early evidence in biogenesis ignited specific steps of being omitted or replaced that eventuate in the individual miRNAs of different mechanisms. Understanding the basic foundation concerning how miRNAs are generated and function will help with diagnostic tools and therapeutic strategies. This review encompasses the canonical and the non-canonical pathways involved in miRNA biogenesis, while elucidating how miRNAs regulate genes at the nuclear level and also the mechanism that lies behind circulating miRNAs.

Stimulants for depression: on the up and up?

The use of traditional psychostimulants (methylphenidate and dexamphetamine) and stimulant-like drugs (modafinil and armodafinil) for the treatment of depression is a growing concern given the lack of research evidence supporting their effectiveness. The current article describes the role of stimulants in treating depression--specifically their risks and benefits and their potential use alongside antidepressants. Clinically, the rapid amelioration of depressive symptoms with traditional psychostimulants is often dramatic but short-lived, and this suggests that they likely operate via different mechanisms to conventional antidepressants. More importantly, there is little evidence from randomised controlled trials supporting their efficacy in treating depression, although modafinil has been shown to be effective in reducing prominent depressive symptoms, such as fatigue. Research is urgently required to clarify psychostimulants' mechanisms of action and to evaluate their long-term benefits and risks in the treatment of major and bipolar depression. Ultimately, specificity of action needs to be determined to inform the sophisticated clinical use of psychostimulants in the management of depression. Until then they should only be prescribed if absolutely necessary, and even then their prescription should be facilitatory and time limited unless it is for investigational purposes.

Financial systems and mechanisms of growth in different conditions of country risk

This article uses panel data from 1976 to 2003 to investigate the ways in which banking and stock markets influence economic growth in situations of high and low country risk. The mean and Standard Deviation (SD) of country risk are adopted to classify 28 countries into Low Risk Low Volatility (LRLV) and High Risk High Volatility (HRHV) subgroups. Through the technique of error correction-based panel co-integration developed by Westerlund (2007), several results are obtained. First, LRLV countries can expand the capitalization of stock market to enhance long-term economic growth. Second, HRHV countries, on the other hand, use two distinct strategies to promote long-term economic growth. Initially they develop their equity markets, which promote economic growth directly. Strengthened equity markets, in turn, aid in the development of credit markets, which subsequently brings an economic boom. Finally, regardless of selected subgroups, the contribution of stock market capitalization to economic growth appears to be substantially larger than that of bank credit, highlighting the importance of stock markets.

Mechanisms underpinning use of new walking and cycling infrastructure in different contexts: mixed-method analysis

BACKGROUND: Few studies have evaluated the effects of infrastructural improvements to promote walking and cycling. Even fewer have explored how the context and mechanisms of such interventions may interact to produce their outcomes. METHODS: This mixed-method analysis forms part of the UK iConnect study, which aims to evaluate new walking and cycling routes at three sites - Cardiff, Kenilworth and Southampton. Applying a complementary follow-up approach, we first identified differences in awareness and patterns of use of the infrastructure in survey data from a cohort of adult residents at baseline in spring 2010 (n = 3516) and again one (n = 1849) and two (n = 1510) years later following completion of the infrastructural projects (Analysis 1). We subsequently analysed data from 17 semi-structured interviews with key informants to understand how the new schemes might influence walking and cycling (Analysis 2a). In parallel, we analysed cohort survey data on environmental perceptions (Analysis 2b). We integrated these two datasets to interpret differences across the sites consistent with a theoretical framework that hypothesised that the schemes would improve connectivity and the social environment. RESULTS: After two years, 52% of Cardiff respondents reported using the infrastructure compared with 37% in Kenilworth and 22% in Southampton. Patterns of use did not vary substantially between sites. 17% reported using the new infrastructure for transport, compared with 39% for recreation. Environmental perceptions at baseline were generally unfavourable, with the greatest improvements in Cardiff. Qualitative data revealed that all schemes had a recreational focus to varying extents, that the visibility of schemes to local people might be an important mechanism driving use and that the scale and design of the schemes and the contrast they presented with existing infrastructure may have influenced their use. CONCLUSIONS: The dominance of recreational uses may have reflected the specific local goals of some of the projects and the discontinuity of the new infrastructure from a satisfactory network of feeder routes. Greater use in Cardiff may have been driven by the mechanisms of greater visibility and superior design features within the context of an existing environment that was conducive neither to walking or cycling nor to car travel.