Direct evidence of oxidative damage in acute and chronic phases of experimental colitis in rats

During inflammatory colitis in man and experimental animals, the production of free radicals increases. This study evaluated the histological pattern and biochemical parameters of oxidative damage during acute and chronic colitis induced by 2,4,-trinitrobenzenesulfonic acid + ethanol in rats. On the samples of scraped mucosa of six groups of rats, one not treated, one killed after 1 hr, and those killed one, two, four, and eight weeks after the induced-damage, we determined the histological and superoxide dismutase activity and the concentration of lipoperoxides, malonyldialdheyde, and reduced glutathione. After 1 hr, the mucosal damage and superoxide dismutase activity were slight; glutathione, lipoperoxides, and malonyldialdheyde were significantly increased. At one week, the histological damage was severe, decreasing progressively, and significantly correlated to superoxide dismutase activity. Lipoperoxides and malonyldialdheyde were high throughout the study. Glutathione was significantly increased at one and two weeks and dramatically decreased thereafter. Therefore, in experimental colitis the cascade of free-radical production induces a constant self-maintaining lipoperoxidation and consumes the cellular antioxidant capability.     

Inflammatory bowel disease. 1. Origins, presentation, and course

The exact source of interference with the normal protective immune response in patients with inflammatory bowel disease remains unclear. Infectious causes have been proposed, and the increased incidence among family members indicates genetic predisposition. No matter what the pathogenesis may be, the disease is chronic, recurrent, and destructive in many cases. Conventional therapy with 5-ASAs, corticosteroids, immunomodulating agents, methotrexate, and antibiotics often offers relief. However, adverse effects accompany long-term use of many of these agents, so follow-up is important. Much investigation of alternative methods is under way, and anecdotal as well as published experience suggests benefits in at least some patients. Because of the chronic nature of their condition, patients with inflammatory bowel disease often become quite sophisticated in their understanding of treatment methods. Therefore, they should be told of updates regarding new options for disease control. We recommend that patients be seen periodically by a gastroenterologist who has expertise in inflammatory bowel disease, even when the disease is quiescent. Our experience in observing these patients over time strongly supports use of some of the agents discussed in this article for prophylaxis against flares and chronic inflammation.     

Involvement of Fas-mediated apoptosis in the inhibitory effects of interferon-alpha in chronic myelogenous leukemia

Interferon-alpha (IFN-alpha) is an established treatment for chronic myelogenous leukemia (CML) in chronic phase, but the mechanism of its antileukemic activity is not clear. One possible mechanism of action might include the induction of apoptosis, and especially Fas-mediated cell killing may play an important role in the elimination of malignant cells. We investigated Fas receptor (Fas-R) expression and the consequences of Fas-R triggering in CML patients. Using two-color flow cytometry, we found a significantly higher number of Fas-R-expressing CD34+ cells in the bone marrow (BM) of CML patients compared with normal subjects. We have previously shown that IFN-gamma induces Fas-R expression on CD34+ cells; in this study, we investigated whether IFN-alpha induces Fas-R expression on CML progenitor cells. Dose-dependent induction of Fas-R expression was observed after IFN-alpha stimulation of CD34+ cells from CML BM. In methylcellulose culture, IFN-alpha alone at a therapeutic concentration showed only marginal antiproliferative effects on both normal and CML BM progenitors. In contrast, a Fas-R agonist, the anti-CD95 monoclonal antibody CH11, inhibited colony formation from normal progenitors, and the inhibition was even stronger on CML progenitors. When CML BM cells were cultured in the presence of IFN-alpha, Fas-R-mediated inhibition of colony growth was potentiated in a dose-dependent fashion, consistent with IFN-alpha induction of Fas-R expression. This functional effect did not require the presence of accessory cells, since similar results were obtained with purified CD34+ cells. In suspension cultures, we demonstrated that suppression of CML hematopoiesis by IFN-alpha and Fas-R agonist was exerted through Fas-R-mediated induction of apoptosis. Our findings suggest that the Fas-R/Fas-ligand system might be involved in the immunologic regulation of CML progenitor growth and that its effect can be amplified by IFN-alpha.     

Shock-loading response of 6061- T6 aluminum metal-matrix composites

The purpose of this research was to systematically study the influence of peak-shock pressure and second-phase reinforcement on the structure/property response of shock-loaded 6061-T6 Al-alumina composites. The reload stress-strain response of monolithic 6061-T6 Al, used as a baseline for comparison, showed no increased shock hardening compared to the unshocked material deformed to an equivalent strain. The reload stress-strain response of the shock-loaded 6061-T6 Al-alumina composites exhibited a lower reload yield strength than the flow stress of the starting composites. The degree of strength loss was found to increase with increasing shock pressure. Wavespeed measurements of shock-prestrained specimens showed no degradation compared to unshocked specimens, indicating that particle cracking had not occurred under shock. This result was supported by optical metallography, which did not reveal cracked particles or particle decohesion in the shock-prestrained samples. The reload stress-strain response of the shock-prestrained composites, after resolutionizing and T6 reaging, showed that the composites recovered their full as-received preshock stress-strain responses. This result supports the finding that degradation in reload strength was attributable to matrix microstructural changes resulting from the shock. Transmission electron microscopy (TEM) examination of the shock-loaded microstructures revealed that the matrix regions adjacent to the particle/matrix interface had undergone significant recovery and partial recrystallization resulting from the shock. This type of near-interface substructure is in stark contrast to the heavily dislocated near-interface dislocation substructure of the as-received composites. The loss of dislocation density(i.e., strain hardening) in the near-interface matrix region, resulting from the shock, highlights the importance of the thermally introduced dislocation substructure changes in establishing the strength of metal-matrix composites (MMCs). This article is based on a presentation made in the symposium “Dynamic Behavior of Materials,” presented at the 1994 Fall Meeting of TMS/ASM in Rosemont, Illinois, October 3-5, 1994, under the auspices of the TMS-SMD Mechanical Metallurgy Committee and the ASM-MSD Flow and Fracture Committee.     

Experimental test of loss calculations for thin laminations in the presence of normal sinusoidal flux

Recently a variational procedure was developed for calculating losses in thin laminations of any shape in the presence of sinusoidal flux directed normal to the lamination plane. The results for a variety of shapes showed that these losses do not depend on the magnetic characteristics of the lamination material but only on the resistivity. The loss formula is tested experimentally for rectangular shaped laminations for a variety of magnetic and nonmagnetic materials. We obtained good agreement with the prediction both in terms of parameter dependencies and absolute numerical values of the specific losses.     

Binding of Antitumor Ruthenium(III) Complexes to Plasma Proteins

Presently, there is large interest in analysing the interactions in vitro with plasma proteins of some novel antitumor ruthenium(III) complexes that are in preclinical or clinical phase. The joint application of separation and spectroscopic techniques provides valuable information on the nature and the properties of the resulting ruthenium/protein adducts. Recent work carried out in our laboratory points out that, under physiological conditions, some selected ruthenium(III) complexes bind plasma proteins tightly with a marked preference for surface imidazole groups. Representative examples of interactions of antitumor ruthenium(III) complexes with plasma proteins such as albumin and transferrin are given. Notably the antitumor ruthenium(III) complexes considered here bind proteins much tighter than DNA; it is proposed that protein binding of ruthenium(III) complexes will have a large impact on the biodistribution, the pharmacokinetics and the mechanism of action of these experimental drugs.     

Squaramide-Tethered Sulfonamides and Coumarins: Synthesis,Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations

(1) Background: carbonic anhydrases (CAs) are attractive targets for the development of new anticancer therapies; in particular, CAs IX and XII isoforms are overexpressed in numerous tumors. (2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a pharmacophore responsible for the CA inhibition (aryl sulfonamide, coumarin). As a linker, we have used squaramides, featured with strong hydrogen bond acceptor and donor capacities. (3) Results: Starting from easily accessible dimethyl squarate, the title compounds were successfully obtained as crystalline solids, avoiding the use of chromatographic purifications. Interesting and valuable SARs could be obtained upon modification of the length of the hydrocarbon chain, position of the sulfonamido moiety, distance of the aryl sulfonamide scaffold to the squaramide, stereoelectronic effects on the aromatic ring, as well as the number and type of substituents on C-3 and C-4 positions of the coumarin. (4) Conclusions: For sulfonamides, the best profile was achieved for the m-substituted derivative 11 (K_i = 29.4, 9.15 nM, CA IX and XII, respectively), with improved selectivity compared to acetazolamide, a standard drug. Coumarin derivatives afforded an outstanding selectivity (K_i > 10,000 nM for CA I, II); the lead compound (16c) was a strong CA IX and XII inhibitor (K_i = 19.2, 7.23 nM, respectively). Docking simulations revealed the key ligand-enzyme interactions.     

Non‐Celiac Gluten Sensitivity: How Its Gut Immune Activation and Potential Dietary Management Differ from Celiac Disease

Non‐celiac gluten sensitivity (NCGS) is a clinical entity triggered by the ingestion of gluten‐containing grains leading to intestinal and/or extraintestinal symptoms that resolve once the gluten‐containing foodstuff is eliminated from the diet, and it is diagnosed when celiac disease (CD) and wheat allergy (WA) have been ruled out. The limited knowledge about the pathophysiology of NCGS and the lack of validated biomarkers are still major limitations for clinical studies, making it difficult to differentiate NCGS from other gluten‐related disorders (GRD). In the absence of clear‐cut diagnostic criteria, NCGS is still mainly a diagnosis of exclusion. Several studies suggest that NCGS is an immune‐mediated disease that likely activates an innate immune response. Moreover, it has recently been hypothesized that in addition to gluten, other components of wheat may be responsible for the symptoms observed in individuals without CD. This review aims at discussing available evidence related to the histological and immunological features in the gut mucosa of patients with NCGS and at outlining new dietary opportunities for these patients.