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In this minireview, we refer to recent results as far as the Platelet Activating Factor (PAF) inhibitors are concerned. At first, results of organic compounds (natural and synthetic ones and specific and nonspecific) as inhibitors of PAF are reported. Emphasis is given on recent results about a new class of the so-called metal-based inhibitors of PAF. A small library of 30 metal complexes has been thus created; their anti-inflammatory activity has been further evaluated owing to their inhibitory effect against PAF in washed rabbit platelets (WRPs). In addition, emphasis has also been placed on the identification of preliminary structure-activity relationships for the different classes of metal-based inhibitors.

Laminin, a basement membrane protein derived from the matrix of the Engelbreth-Holm-Swarm murine tumor, was nonenzymatically glycosylated in vitro in the presence of increasing glucose concentrations. The amount of glucose incorporated per laminin molecule was shown to be proportional to the molarity of glucose used. Nonenzymatic glycosylation resulted in formation of cross-links and alterations of the cruciform shape of laminin molecules; these alterations were dramatic when high concentrations of glucose were used. One of the functions of laminin, the process of self-assembly, was shown to be impaired after in vitro nonenzymatic glycosylation. Glucose incorporation resulted in a dramatic decrease of long-to-long laminin dimers, which normally form during the initial steps of assembly. Furthermore, nonenzymatic glycosylation of laminin reduced its ability to self-associate into complexes larger than dimers, as judged by turbidimetry. The observed decrease of maximal turbidity was proportional to the degree of nonenzymatic glycosylation. Aminoguanidine, which has been suggested to inhibit cross-link formation, was shown to restore to a large extent the shape of laminin, the percentage of long-to-long arm dimers, and the maximal turbidity when included in the mixtures of laminin and glucose. These data suggest that structural and functional alterations of laminin may be primarily due to formation of cross-links. Such modifications of laminin (along with our basement membrane components) may contribute to the morphological and physiological changes observed in basement membranes under diabetic conditions.

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J. Neurochem. (2010) 115, 873–884. Abstract Apolipoprotein E (apoE) plays a crucial role in lipid transport in circulation and the brain. The apoE4 isoform is a major risk factor for Alzheimer’s disease (AD). ApoE4 is more susceptible to proteolysis than other apoE isoforms and apoE4 fragments have been found in brains of AD patients. These apoE4 fragments have been hypothesized to be involved in the pathogenesis of AD, although the mechanism is not clear. In this study we examined the effect of lipid‐free apoE4 on amyloid precursor protein processing and 40‐amino‐acid Aβ variant and 42‐amino‐acid Aβ variant levels in human neuroblastoma SK‐N‐SH cells. We discovered that a specific apoE4 fragment, apoE4[Δ(166‐299)], can promote the cellular uptake of extracellular 40‐amino‐acid Aβ variant and 42‐amino‐acid Aβ variant either generated after amyloid precursor protein transfection or added exogenously. A longer length fragment, apoE4[Δ(186‐299)], or full‐length apoE4 failed to elicit this effect. ApoE4[Δ(166‐299)] effected a 20% reduction of cellular sphingomyelin levels, as well as changes in cellular membrane micro‐fluidity. Following uptake, approximately 50% of 42‐amino‐acid Aβ variant remained within the cell for at least 24 h, and led to increased formation of reactive oxygen species. Overall, our findings suggest a direct link between two early events in the pathogenesis of AD, apoE4 proteolysis and intraneuronal presence of amyloid beta peptide.

Liraglutide, a human long‐lasting GLP‐1 analogue, is currently regarded as a powerful treatment option for type 2 diabetes. Apart from glucoregulatory and insulinotropic actions, liraglutide increases β‐cell mass through stimulation of β‐cell proliferation and islet neogenesis, as well as inhibition of β‐cell apoptosis. However, the underline molecular mechanisms have not been fully characterized. In this study, we investigated the mechanism by which liraglutide preserves islet β‐cells in an animal model of overt diabetes, the obese db/db mice, and protects a mouse pancreatic β‐cell line (βTC‐6 cells) against apoptosis. Treatment of 12‐week‐old diabetic mice with liraglutide for 2 weeks had no appreciable effects on blood non‐fasting glucose concentration, islet insulin content and body weight. However, morphological and biochemical examination of diabetic mouse pancreatic islets demonstrated that liraglutide restores islet size, reduces islet β‐cell apoptosis and improves nephrin expression, a protein involved in β‐cell survival signalling. Our results indicated that liraglutide protects βTC‐6 cells from serum withdrawal‐induced apoptosis through inhibition of caspase‐3 activation. The molecular mechanism of the anti‐apoptotic action of liraglutide in βTC‐6‐cells comprises stimulation of PI3‐kinase‐dependent AKT phosphorylation leading to the phosphorylation, hence inactivation of the pro‐apoptotic protein BAD and inhibition of FoxO1 transcription factor. In conclusion, we provided evidence that the GLP‐1 analogue liraglutide exerts important beneficial effects on pancreatic islet architecture and β‐cell survival by protecting cells against apoptosis. These findings extend our understanding of the actions of liraglutide and further support the use of GLP‐1R agonists in the treatment of patients with type 2 diabetes.

Colored tracers, injected intraperitoneally in mice, are taken up by diaphragmatic lymphatics, outlining their large, terminal cisterns, the so-called lacunae. The lacunae occur exclusively on the muscular portion of the diaphragm. The mesothelium covering non-lacunar and lacunar areas of the muscular portion was examined with the SEM. Mesothelial cells overlying non-lacunar areas are extremely flat, and their boundaries are indistinct. Mesothelial cells overlying lacunae protrude towards the lumen of the peritoneal cavity and have distinct outlines. There are openings or stomata, 4-12 micron in diameter, between them. Some of the stomata overlie a deep pit; others overlie a shallower pit in which the surface of another cell can be seen beneath the opening. It seems likely that the bulk of the fluid draining from the peritoneal cavity passes through these stomata into underlying lymphatic lacunae.