Chronic Stress Induces Sex-Specific Alterations in Methylation and Expression of Corticotropin-Releasing Factor Gene in the Rat

Contains fulltext : 91627.pdf (publisher's version ) (Open Access

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Capsule endoscopy for the detection of oesophageal mucosal disorders: a comparison of two different ingestion protocols

OBJECTIVE: To assess the accuracy of a new ingestion protocol for capsule endoscopy (CE) in evaluating patients with gastro-oesophageal reflux disease (GORD). METHODS: Oesophago-gastroduodenoscopy (OGD) was performed 1 week prior to CE. The first 28 subjects swallowed the capsule following the original ingestion protocol (OIP) and the subsequent 30 subjects following a simplified ingestion protocol (SIP). CE videos were reviewed by two independent investigators who were blinded to the OGD findings. RESULTS: Of 48 patients included, 24 were diagnosed with reflux oesophagitis (67% male, mean age 49.5+/-13 years) and 24 with Barrett oesophagus (BO) (88% male, 55.6+/-10 years) by OGD. In addition, 10 asymptomatic healthy controls (50% male, 45.8+/-7.1 years) were included. Oesophageal transit time was faster in patients using the SIP compared to the OIP (126+/-26 s versus 214+/-33; p=0.04). Complete evaluation of the Z-line was possible in 19/28 (68%) of the OIPs compared to 28/30 (93%) of the SIPs (p=0.04). Sensitivity for detecting any oesophageal abnormality was higher in the SIP group than in the OIP group (97% versus 89%; p=0.11). Overall, CE detected oesophagitis in 22/24 patients (sensitivity, 92%; specificity, 88%) and BO in 23/24 patients (sensitivity, 96%; specificity, 91%). Furthermore, 41/44 (93%) preferred CE over OGD and experienced less discomfort and pain during CE. CONCLUSION: CE is an accurate method for detecting mucosal oesophageal abnormalities. The new ingestion protocol improves the visualization of the Z-line, which is likely to increase the diagnostic yield of C

Conditions influencing the in vitro antifungal activity of lactoferrin combined with antimycotics against clinical isolates of Candida - Impact on the development of buccal preparations of lactoferrin

Lactoferrin, an iron-binding glycoprotein, is a potential agent for the treatment of oropharyngeal Candidiasis. The aim of the present study was to test the capability of lactoferrin, combined or not combined with conventional antifungal agents, to inhibit the growth of different Candida species under various experimental conditions to be of guidance in the development of a suitable pharmaceutical formulation containing lactoferrin. The anti-Candida activities of lactoferrin were considerably higher using RPMI instead of SLM as assay medium. They were moreover increased by raising the medium pH from 5.6 to 7.5. With the 'standard' antifungal agent fluconazole similar results were found as for lactoferrin, but the medium type and pH did not affect MIC values of amphotericin B. The addition of saliva to medium did not reduce the antifungal activities of the individual compounds. Synergistic inhibitory effects on Candida growth were found for combinations of lactoferrin and fluconazole or amphotericin B, irrespective of the medium type and pH, or the addition of saliva. This indicates that for treatment of oral Candidiasis a formulation containing lactoferrin seems appropriate; results may be optimized if the formulation is provided with buffer capacity to attain pH 7.5 in the mucosal fluid. The synergistic effects between lactoferrin and 'standard' antifungals indicate that combinations should be considered in such a formulation

In vivo uptake and processing of liposomes by parenchymal and non-parenchymal liver cells:Application to Immunotherapeutic Treatment of Hepatic Metastases

Many early investigations on the in vivo fate of intravenously injected liposomes have pointed to the liver as the major organ responsible for elimination from the circulatory system. For several years now we have made detailed studies on the participation of various cell types of the liver, mainly macrophages and hepatocytes, in the hepatic uptake and processing of liposomes, both in vivo and in vitro

Org 214007-0: a novel non-steroidal selective glucocorticoid receptor modulator with full anti-inflammatory properties and improved therapeutic index

Contains fulltext : 103595.pdf (publisher's version ) (Open Access)Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects