Inhibitory effect of albumin-derived advanced glycosylation products on PMA-induced superoxide anion production by rat macrophages

Advanced glycosylation end products (AGE) are implicated in many of the complications of diabetes. In the same way, infectious diseases are frequently associated with this disease. An impaired respiratory burst in macrophages may be a cause of infectious complications in diabetic patients. To establish a possible mechanism of this altered cell function, we have analyzed the effect of AGE-modified proteins on PMA-dependent superoxide anion production (O2.-) from normal rat peritoneal macrophages. We have used AGE-modified bovine serum albumin (AGE-BSA) prepared by incubation with glucose. AGE-BSA partially inhibits the phorbol ester-dependent superoxide production by macrophages in vitro. The specificity of this inhibitory effect is demonstrated by the fact that aminoguanidine, an inhibitor of the formation of AGE products, fully prevents the effect of AGE-BSA in vitro. Macrophages from diabetic rats shown an inhibition on PMA dependent-O2.- production. However, the treatment in vivo with aminoguanidine produced a cancelation of the inhibitory effect observed in the diabetic state. These data suggest that AGE-modified proteins could be implicated in the impairment of macrophage respiratory burst in diabetes.     

Heat pipes with self-rewetting fluids under low-gravity conditions

The work presents experimental tests about the performance of heat pipes filled with a “self-rewetting“ fluid (alcohol aqueous solutions). Comparison with conventional commercial water heat pipes is also considered. The used fluid exhibits an anomalous increase in the surface tension with increasing temperature. Along these lines, the fluid has been investigated as a possible means to improve heat transfer inside the heat pipes with a focus, in particular, on space applications (next generation satellites). The experiments have been carried out both in normal and in low-gravity conditions (attained onboard a ‘zero-g’ plane, during a parabilic flight campaign). The results have confirmed improved capability of the considered heat pipes with respect to traditional heat pipes filled with water.     

Molecular Determinants of Soft Tissue Sarcoma Immunity: Targets for Immune Intervention

Soft tissue sarcomas (STSs) are a family of rare malignant tumors encompassing more than 80 histologies. Current therapies for metastatic STS, a condition that affects roughly half of patients, have limited efficacy, making innovative therapeutic strategies urgently needed. From a molecular point of view, STSs can be classified as translocation-related and those with a heavily rearranged genotype. Although only the latter display an increased mutational burden, molecular profiles suggestive of an “immune hot” tumor microenvironment are observed across STS histologies, and response to immunotherapy has been reported in both translocation-related and genetic complex STSs. These data reinforce the notion that immunity in STSs is multifaceted and influenced by both genetic and epigenetic determinants. Cumulative evidence indicates that a fine characterization of STSs at different levels is required to identify biomarkers predictive of immunotherapy response and to discover targetable pathways to switch on the immune sensitivity of “immune cold” tumors. In this review, we will summarize recent findings on the interplay between genetic landscape, molecular profiling and immunity in STSs. Immunological and molecular features will be discussed for their prognostic value in selected STS histologies. Finally, the local and systemic immunomodulatory effects of the targeted drugs imatinib and sunitinib will be discussed.     

Compaction pressure influence on material properties and sorption behaviour of LiBH4–MgH2 composite

Among different Reactive Hydride Composites (RHCs), the combination of LiBH₄ and MgH₂ is a promising one for hydrogen storage, providing a high reversible storage capacity. During desorption of both LiBH₄ and MgH₂, the formation of MgB₂ lowers the overall reaction enthalpy. In this work, the material was compacted to pellets for further improvement of the volumetric hydrogen capacity. The influence of compaction pressure on the apparent density, thermal conductivity and sorption behaviour for the Li-based RHC during cycling was investigated for the first time. Although LiBH₄ melts during cycling, decrepitation or disaggregation of the pellets is not observed for any of the investigated compaction pressures. However, a strong influence of the compaction pressure on the apparent hydrogen storage capacity is detected. The influence on the reaction kinetics is rather low. To provide explanations for the observed correlations, SEM analysis before and after each sorption step was performed for different compaction pressures. Thus, the low hydrogen sorption in the first cycles and the continuously improving sorption for low pressure compacted pellets with cycling may be explained by some surface observations, along with the form stability of the pellets.     

Scalaradial, a dialdehyde-containing marine metabolite that causes an unexpected noncovalent PLA2 Inactivation

Several marine terpenoids that contain at least one reactive aldehyde group, such as manoalide and its congeners, possess interesting anti-inflammatory activities that are mediated by the covalent inactivation of secretory phospholipase A(2) (sPLA(2)). Scalaradial, a 1,4-dialdehyde marine terpenoid that was isolated from the sponge Cacospongia mollior, is endowed with a relevant anti-inflammatory profile, both in vitro and in vivo, through selective sPLA(2) inhibition. Due to its peculiar dialdehyde structural feature, it has been proposed that scalaradial exerts its enzymatic inactivation by means of an irreversible covalent modification of its target. In the context of our on-going research on anti-PLA(2) natural products and their interaction at a molecular level, we studied scalaradial in an attempt to shed more light on the molecular mechanism of its PLA(2) inhibition. A detailed analysis of the reaction profile between scalaradial and bee venom PLA(2), a model sPLA(2) that shares a high structural homology with the human synovial enzyme, was performed by a combination of spectroscopic techniques, chemical reactions (selective modifications, biomimetic reactions), and classical protein chemistry (such as proteolytic digestion, HPLC and mass spectrometry), along with molecular modeling studies. Unexpectedly, our data clearly indicated the noncovalent forces to be the leading event in the PLA(2) inactivation process; thus, the covalent modification of the enzyme emerges as only a minor side event in the ligand-enzyme interaction. The overall picture might be useful in the design of SLD analogues as new potential anti-inflammatory compounds that target sPLA(2) enzymes.     

Inhibition of Bcr-Abl phosphorylation and induction of apoptosis by pyrazolo[3,4-d]pyrimidines in human leukemia cells

A series of pyrazolo[3,4-d]pyrimidines, previously found to be Src inhibitors, was tested for their ability to inhibit proliferation of three Bcr-Abl-positive human leukemia cell lines (K-562, KU-812, and MEG-01), on the basis of the experimental evidence that various Src inhibitors are also active against Bcr-Abl kinase (the so called dual Src/Abl inhibitors). They reduce Bcr-Abl tyrosine phosphorylation and promote apoptosis of the Bcr-Abl-expressing cells. A cell-free enzymatic assay on isolated c-Abl confirmed that such compounds directly inhibit Abl activity. Finally, molecular modeling simulations were also performed to hypothesize the binding mode of the compounds into the Abl binding site.