Synthesis and molecular modeling studies of 3-chloro-4-substituted-1-(8-hydroxy-quinolin-5-yl)-azetidin-2-ones as novel anti-filarial agents

A series of 3-chloro-4-substituted-1-(8-hydroxy-quinolin-5-yl)-azetidin-2-ones were synthesized and evaluated for their in vitro anti-filarial activity. To pre-assess the anti-filarial behavior of synthesized compounds (V_a–f) on a structural basis, automated docking studies were carried out with Molecular Design Suite (MDS v 3.5) into the active site of glutathione-S-transferase (GST) enzyme; scoring functions of these compounds at the active site of the GST enzyme were used for correlation with observed activity. Compounds V_e and V_f have shown good affinity for receptor GST, as well as in vitro anti-filarial potency.     

Flying Over an Infected Landscape: Distribution of Highly Pathogenic Avian Influenza H5N1 Risk in South Asia and Satellite Tracking of Wild Waterfowl

Highly pathogenic avian influenza (HPAI) H5N1 virus persists in Asia, posing a threat to poultry, wild birds, and humans. Previous work in Southeast Asia demonstrated that HPAI H5N1 risk is related to domestic ducks and people. Other studies discussed the role of migratory birds in the long distance spread of HPAI H5N1. However, the interplay between local persistence and long-distance dispersal has never been studied. We expand previous geospatial risk analysis to include South and Southeast Asia, and integrate the analysis with migration data of satellite-tracked wild waterfowl along the Central Asia flyway. We find that the population of domestic duck is the main factor delineating areas at risk of HPAI H5N1 spread in domestic poultry in South Asia, and that other risk factors, such as human population and chicken density, are associated with HPAI H5N1 risk within those areas. We also find that satellite tracked birds (Ruddy Shelduck and two Bar-headed Geese) reveal a direct spatio-temporal link between the HPAI H5N1 hot-spots identified in India and Bangladesh through our risk model, and the wild bird outbreaks in May-June-July 2009 in China (Qinghai Lake), Mongolia, and Russia. This suggests that the continental-scale dynamics of HPAI H5N1 are structured as a number of persistence areas delineated by domestic ducks, connected by rare transmission through migratory waterfowl.     

<Emphasis Type="Italic">Burkholderia</Emphasis> Hep_Hag autotransporter (BuHA) proteins elicit a strong antibody response during experimental glanders but not human melioidosis

Background  

The bacterial biothreat agents Burkholderia mallei and Burkholderia pseudomallei are the cause of glanders and melioidosis, respectively. Genomic and epidemiological studies have shown that B. mallei is a recently emerged, host restricted clone of B. pseudomallei.     

A long-term "memory" of HIF induction in response to chronic mild decreased oxygen after oxygen normalization

Background

Cardiovascular diseases (CVD) are the leading cause of death and the third cause of disability in Europe. Prevention programmes should include interventions aimed at a reduction of medical risk factors (hypertension, hypercholesterol, hyperglycemia, overweight and obesity) as well as behavioural risk factors (sedentary lifestyle, high fat intake and low fruit and vegetable intake, smoking). The aim of this study is to investigate the effects of a multifaceted, multidisciplinary electronic prevention programme on cardiovascular risk factors.

Methods/Design

In a randomized controlled trial, one group will receive a maximal intervention (= intervention group). The intervention group will be compared to the control group receiving a minimal intervention. An inclusion of 350 patients in total, with a follow-up of 3 years is foreseen. The inclusion criteria are age between 25–65 and insured by the Onderlinge Ziekenkas, insuring for guaranteed income in case of illness for self-employed. The maximal intervention group receives several prevention consultations by their general practitioner (GP) using a new type of cardiovascular risk calculator with personalised feedback on behavioural risk factors. These patients receive a follow-up with intensive support of health behaviour change via different methods, i.e. a tailored website and personal advice of a multidisciplinary team (psychologist, physiotherapist and dietician). The aim of this strategy is to reduce cardiovascular risk factors according to the guidelines. The primary outcome measures will be cardiovascular risk factors. The secondary outcome measures are cardiovascular events, quality of life, costs and incremental cost effectiveness ratios. The control group receives prevention consultations using a new type of cardiovascular risk calculator and general feedback.

Discussion

This trial incorporates interventions by GPs and other health professionals aiming at a reduction of medical and behavioural cardiovascular risk factors. An assessment of clinical, psychological and economical outcome measures will be performed.

Trial registration

ISRCTN23940498     

Effect of licofelone against NSAIDs-induced gastrointestinal ulceration and inflammation

The present study was aimed to evaluate the effect of licofelone, a dual inhibitor of cycloxygenase1/2-5-lipoxygenase against indomethacin-induced gastric damage in rats and mice in order to assess the role of leukotrienes if any, in non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrointestinal inflammation. Acute pretreatment with licofelone reversed the indomethacin-induced gastric ulceration, neutrophil adhesion in mesentery venules, neutrophil count in blood, lipid peroxides and vascularity in the stomachs of mice and rats. Further, chronic pretreatment of licofelone also prevented indomethacin-induced gastric morphological changes and cellular infiltration in mesentery venules. Moreover, acute administration of indomethacin elevated leukotriene B4 levels in gastric mucosa, which was reversed by pretreatment with licofelone The results suggest that licofelone offered gastroprotection against NSAIDs-induced gastropathy through its effect on leukotrienes and by inhibiting extravasation of neutrophils.     

Normal rat hepatic stellate cells respond to endotoxin in LBP-independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes

Endotoxin is implicated in the pathology of acute liver failure. The mechanisms of its actions on quiescent hepatic stellate cells (qHSCs) and their implications in hepatocyte injury are incompletely understood. We investigated effects of endotoxin (bacterial lipopolysaccharide; LPS) on qHSCs and subsequently on hepatocytes. After overnight culture following their isolation, qHSCs were incubated with or without endotoxin for 24 h. The cells and the culture supernatant were analyzed for cytokines and nitric oxide (NO) synthesis. The effects of qHSC-conditioned media on hepatocytes were then determined. LPS increased inducible NO synthase expression, stimulated NO synthesis, and inhibited DNA synthesis in qHSCs. qHSC-conditioned medium inhibited DNA synthesis in hepatocytes without affecting NO synthesis, while LPS (1-1,000 ng/ml)-conditioned qHSC medium stimulated NO synthesis and caused further inhibition of DNA synthesis and apoptosis. These effects of LPS were more pronounced when qHSCs were incubated with serum, but not with LPS-binding protein (LBP) although CD14 (a receptor for LPS-LBP complex) was found in qHSCs. LPS stimulated the synthesis of TNF-alpha, interleukin (IL)-6, and IL-1beta but not of TGF-beta in qHSCs. Individually or together, L-N(G)-monomethylarginine and antibodies to IL-1beta, IL-6, and TNF-alpha only partly reversed qHSC + LPS-conditioned medium-induced inhibition of DNA synthesis in hepatocytes. These results suggest that the effects of LPS on qHSCs are novel, occurring without the aid of LBP/CD14. They also indicate that other factors, in addition to NO, TGF-beta, TNF-alpha, IL-1beta, and IL-6 are involved in the mechanisms of the growth inhibitory effects of qHSCs on hepatocytes.     

Bone formation rather than inflammation reflects Ankylosing Spondylitis activity on PET-CT: a pilot study

Introduction

Positron Emission Tomography - Computer Tomography (PET-CT) is an interesting imaging technique to visualize Ankylosing Spondylitis (AS) activity using specific PET tracers. Previous studies have shown that the PET tracers [¹⁸F]FDG and [¹¹C](R)PK11195 can target inflammation (synovitis) in rheumatoid arthritis (RA) and may therefore be useful in AS. Another interesting tracer for AS is [¹⁸F]Fluoride, which targets bone formation. In a pilot setting, the potential of PET-CT in imaging AS activity was tested using different tracers, with Magnetic Resonance Imaging (MRI) and conventional radiographs as reference.

Methods

In a stepwise approach different PET tracers were investigated. First, whole body [¹⁸F]FDG and [¹¹C](R)PK11195 PET-CT scans were obtained of ten AS patients fulfilling the modified New York criteria. According to the BASDAI five of these patients had low and five had high disease activity. Secondly, an extra PET-CT scan using [¹⁸F]Fluoride was made of two additional AS patients with high disease activity. MRI scans of the total spine and sacroiliac joints were performed, and conventional radiographs of the total spine and sacroiliac joints were available for all patients. Scans and radiographs were visually scored by two observers blinded for clinical data.

Results

No increased [¹⁸F]FDG and [¹¹C](R)PK11195 uptake was noticed on PET-CT scans of the first 10 patients. In contrast, MRI demonstrated a total of five bone edema lesions in three out of 10 patients. In the two additional AS patients scanned with [¹⁸F]Fluoride PET-CT, [¹⁸F]Fluoride depicted 17 regions with increased uptake in both vertebral column and sacroiliac joints. In contrast, [¹⁸F]FDG depicted only three lesions, with an uptake of five times lower compared to [¹⁸F]Fluoride, and again no [¹¹C](R)PK11195 positive lesions were found. In these two patients, MRI detected nine lesions and six out of nine matched with the anatomical position of [¹⁸F]Fluoride uptake. Conventional radiographs showed structural bony changes in 11 out of 17 [¹⁸F]Fluoride PET positive lesions.

Conclusions

Our PET-CT data suggest that AS activity is reflected by bone activity (formation) rather than inflammation. The results also show the potential value of PET-CT for imaging AS activity using the bone tracer [¹⁸F]Fluoride. In contrast to active RA, inflammation tracers [¹⁸F]FDG and [¹¹C](R)PK11195 appeared to be less useful for AS imaging.     

Mechanistic approach for fabrication of gold nanoparticles by Nitzschia diatom and their antibacterial activity

The problem of chemically synthesized nanoproducts motivated scientific community to explore ecofriendly methods of nanosynthesis. Diatoms belong to a group of aquatic, unicellular, photosynthetic microalgae have been scarcely investigated as a source of reducing and capping agents for nanosynthesis of pesticides and antibiotics. The present study reports a novel ecofriendly method for the fabrication of bioactive gold nanoparticles using locally isolated Nitzschia diatoms. The diatom-fabricated gold nanoparticles show characteristic ruby red colored with sharp absorbance peak at 529 nm. Electron microscopy confirmed irregular shape of gold nanoparticles, with average size of 43 nm and zeta potential of −16.8 mV. The effects of gold nanoparticles on diatom viability were investigated using light and electron microscopy. The mechanistic approach to shed light on how diatoms reacted after exposure to gold metal salt revealed that exposure to gold chloride triggers elevated levels of catalase and peroxidase (12.76 and 14.43 unit/mg protein, respectively) to relieve reactive oxygen species (ROS) stress induced by gold salt exposure. Investigation studies on mechanisms behind Nitzschia-mediated gold nanoparticles fabrication outlined the role of diatom proteins, polysaccharides in reduction, and stabilization of nanoparticles as confirmed by FT-IR analysis. Bioactivity of gold nanoparticles was accessed by coupling them with antibiotics (penicillin and streptomycin), which increased their antibacterial activity compared to individual nanoparticles and antibiotics (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). Overall, the present novel phyco-nanotechnological approach is a promising tool to be used as sustainable strategy in green nanotechnology as well as to reduce use of antibiotics in microbial control.