Dendritic cell (DC)-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is a DC-specific C-type lectin that plays an important role in recognizing and capturing pathogens, DC migration and initiation of T cell responses. Here, we show that anti-P-selectin lectin-EGF domain monoclonal antibody (PsL-EGFmAb), originally prepared for blockade of the adhesive molecule P-selectin, significantly down-regulated DC-SIGN expression as well as expression of mature DC-related molecules including CD83, CD86 and CD80 on human DCs. This PsL-EGFmAb treatment of DCs resulted in impaired allogeneic T cell proliferation and IL-12 production. Furthermore, we show that PsL-EGFmAb-induced down-regulation of DC-SIGN may inhibit NF-kappaB expression in DCs, which accounts for the inhibition of DC maturation and stimulatory function. Our present studies indicate that PsL-EGFmAb may be a useful reagent for regulating DC-SIGN expression and DC function.

The presence of a "status quo" hormone like JH has not been found in ticks. The most advanced understanding of tick endocrinology is associated with female reproduction, where the sequence of the first messages for storage proteins (vitellogenin (Vg) and carrier protein), the Vg receptor, and male peptidic pheromones were recently reported. The current consensus model suggests that ecdysteroids from the epidermis regulated by a putative peptidic ecdysiotrophic hormone from the synganlion initiates the expression of the Vg messages in fat body and midgut. Vg protein, secreted into the hemolymph, requires an ovary Vg receptor to be absorbed by oocytes. Male pheromones transferred into the female genital tract during mating initiate blood feeding to repletion and vitellogenesis. The work so far on tick endocrinology is limited by the paucity of identified hormones and the small number of studies on a few tick models. The role of storage proteins in the evolution of hematophagy is discussed.

Tank-Binding-Kinase 1 (TBK-1) has been proposed as a putative mediator in tumor angiogenesis. It was the aim of our study to gain insight into TBK-1s role in tumor angiogenesis and tumor-associated microvascular inflammation. TBK-1 overexpressing KB 3-1 cells were generated and their growth characteristics were analyzed. Expression of TBK-1, VEGF, RANTES and Il-8 were quantified using qPCR and western blot analysis. Intravital microscopy using the dorsal skinfold chamber model in nude mice addressed total (TIVD) and functional intratumoral vascular density (FIVD), perfusion index, vessel diameter and leukocyte sticking. Transfection of KB-3 cells resulted in significantly increased TBK-1, RANTES and IL-8 expression without affecting cellular growth. Supernatants from TBK-1 overexpressing clones induced HUVEC proliferation. Intravital microscopy identified an increase in leukocyte sticking paralleled by significantly increased TIVD and FIVD as a result of increased VEGF expression. Therefore, TBK-1 represents a novel mediator of tumor angiogenesis and exerts proinflammatory effects via upregulation of inflammatory cytokines. The TBK-1 pathway might be an important cross-link between angiogenesis and inflammation representing a possible target for anti-tumor therapy.

The predicted secretome of the opportunistic fungal pathogen Candida albicans contains more than 200 ORFs of diverse and often unknown function. Majority of the secreted proteins that have been experimentally evaluated to date are hydrolytic enzymes (proteinases, phospholipases and lipases). Acting on the interface between the pathogen and the host, the secreted hydrolases may enable invasion of host tissues, help the pathogen to avoid host defense mechanisms, or allow the microorganism to utilize host cell macromolecules as a source of nutrients. Aspartic proteinases constitute the best-characterized family of the C. albicans secreted proteins. Number of studies addressed also secreted phospholipases. Lipases and N-acetylhexosaminidase have received less attention thus far. Many ORFs that are predicted to encode secreted proteins await characterization.

Mounting body of evidence indicates that the disruption of epithelial tight junctions and resulting loss of barrier function play a crucial role in the pathogenesis of a variety of gastrointestinal, hepatic, pulmonary, kidney and ocular diseases. Increased production of inflammatory mediators such as cytokines and reactive oxygen species disrupt the epithelial and endothelial barrier function by destabilizing tight junctions. Oxidative stress induced by various reactive oxygen species such as hydrogen peroxide, nitric oxide, peroxynitrite and hypochlorous acid disrupt the epithelial and endothelial tight junctions in various tissues. The mechanism involved in oxidative stress-induced disruption of tight junction includes protein modification such as thiol oxidation, phosphorylation, nitration and carbonylation. The role of signaling molecules such as protein kinases and protein phosphatases in regulation of tight junctions is discussed in this article. Understanding such mechanisms in oxidative stress-induced disruption of epithelial and endothelial barrier functions is likely to provide insight into the pathogenesis of various inflammatory diseases, and may form a basis for the design of treatment strategies for different diseases.

Stretch induces biphasic inotropic effects in mammalian myocardium. A delayed component (slow force response, SFR) has been demonstrated in various species, however, experimental conditions varied and the underlying mechanisms are controversial. The physiological relevance of the SFR is poorly understood. Experiments were performed in ventricular muscle strips from failing human hearts and non-failing rabbit hearts. Upon stretch, twitch force was assessed at basal conditions (1 Hz, 37 degrees C) and after changing stimulation frequency with and without blockade of the Na+/H+-exchanger-1 (NHE1) or reverse-mode Na+/Ca2+-exchange (NCX). Action potential duration (APD) was assessed using floating electrodes. Low stimulation rates (0.2 Hz) potentiated and higher stimulation rates (2 and 3 Hz) reduced the SFR. The extent of SFR inhibition by NHE1 or NCX inhibition was not affected by stimulation rate. APD decreased at 0.2 Hz but was not altered at higher stimulation rates. The data demonstrate frequency-dependence of the SFR with greater positive inotropic effects at lower stimulation rates. Subcellular mechanisms underlying the SFR are not fundamentally affected by stimulation rate. The SFR may have more pronounced physiological effects at lower heart rates.

MMPs are zinc-dependent endopeptidases that are involved in proteolysis of extracellular matrix in both physiological and pathological processes including cancer. MMPs are involved at all stages of tumor progression, including tumor growth, angiogenesis, and metastasis. We recently showed that overexpression of Lefty in cancer cells restrains tumor growth. Here, we show that small forms of Lefty are generated by MMP2 (gelatinase A) mediated cleavage. In turn, these forms of Lefty strongly inhibit the autocatalytic, gelatinolytic and caseinolytic activities of MMP2 in vitro. We show that a short synthesized form of Lefty peptide (CASDGALVP) inhibits gelatinolytic and caseinolytic activities of MMP2 in vitro and inhibits tumor growth in vivo. Together, these findings show that lefty peptides are a new class of gelatinase A inhibitors that restrain tumor growth.

The 26S proteasome is an abundant multi-subunit complex, which, in addition to lysosomes, represents a major cellular "protein degradation factory". The proteasome complex possesses protease, ATPase/helicase, and RNAse enzymatic activities, which are used by the latter to regulate various physiological processes. Recent findings have revealed an important role of proteasomes in transcriptional regulation. Although proteasomes are well documented to undergo various post-translational modifications, little is known about their functional significance, in particular in the process of gene regulation in response to various forms of stress. Here, we review the data on the role of proteasomes in gene regulation and their post-translational modifications as well as discuss potential mechanisms by which proteasomal activity may be regulated by genotoxic stress.

Hepatitis E virus (HEV) is responsible for large waterborne epidemics of acute hepatitis in endemic regions and for sporadic autochthonous cases in non endemic regions. Although the water vector has been thoroughly documented in endemic regions, very little is known about the modes of contamination occurring in non endemic regions. Unlike the other hepatitis viruses, HEV has an animal reservoir. Several lines of evidence, such as the results of phylogenic analysis and studies on direct contamination via infected food products, have suggested that some cases of animal to human transmission occur. However, all the possible sources of human contamination in non endemic areas have not yet been defined, and this point needs to be investigated. The high genetic variability of HEV, which might be an important factor, involved in zoonotic contamination processes, also needs a surveillance plan.

The Islets of Langerhans form a nutrient sensing network spread throughout the pancreas. They are tightly connected to the source organ, the intestine, and the target organs--liver, muscle, and fat cells. The expression of a unique set of proteins enables beta cells, the most frequent islet cell type, to detect elevated blood glucose levels and secrete insulin accordingly. Clustered beta-cells achieve tighter regulation of glucose-induced insulin secretion by coordination through cell surface proteins. They also adjust their secretory capacity and flow to avoid being damaged. The immediate reaction of the beta cell to nutrients is regulated by translational mechanisms, while longer term adaptations involve changes in transcription. Glucose increases overall protein synthesis in beta-cells but selectively boosts translation of some secretory proteins including insulin. This may be mediated through recognition of RNA motifs in the untranslated regions of those messengers. If essential molecular components of this nutrient sensing system are broken or fail due to repeated stress, beta cells malfunction, which on a larger scale manifest as diseases like diabetes mellitus.

This study is to examine our hypothesis that CD4+CD25(high)Foxp3+ regulatory T cells (Tregs) have an interleukin-2 (IL-2) withdrawal-triggered apoptosis pathway, and modulation of Treg apoptosis pathway affects development of vascular inflammation. We found that pro-apoptotic protein Bax upregulation in Tregs is induced by IL-2 withdrawal. Treg apoptosis induced by IL-2 withdrawal is inhibited by a Bax inhibitor, suggesting that highly expressed Bax is functional. To define the role of upregulated Bax in Treg apoptosis, we established a Tregs-specific Bax transgenic mouse model. Enforced expression of Bax in Tregs promotes Treg apoptosis triggered by IL-2 withdrawal and other apoptosis stimuli, suggesting pro-apoptotic role of highly expressed Bax in wild-type Tregs. Finally, higher expression of Bax in Tregs decreases the striking threshold of vascular inflammation due to the failure of suppression of inflammatory cells resulting from Treg apoptosis. These results have demonstrated the proof of principle that the modulation of Tregs apoptosis/survival could be used as a new therapeutic approach for inflammatory cardiovascular diseases.

Proteins that combine PML NBs (ND10) can be divided into two groups: "transient" (that accumulate at PML NBs upon over-expression, interferon-induced up-regulation, block of proteosomal degradation, environmental stress or viral infection) and "constitutive" that co-localize with PML in the majority of cultured cells. One of the few "constitutive" components of PML NBs is the death domain-associated protein Daxx. While PML NBs are the most obvious depositories of Daxx, there are multiple alternative localization of this protein in the nucleus and cytoplasm, suggesting differential functionality of Daxx at different cellular compartments and stages of the cell cycle. The purpose of this review is to analyze Daxx spatiotemporal behavior within and outside of PML NBs and to discuss functions attributed to these localizations. We suggest that Daxx can participate in numerous cellular functions as a mediator of protein interactions, thus acting as a fine tuning instrument in highly orchestrated cellular processes; we also envision PML NBs accumulation of Daxx as an "out of action" storage depot.

Focal adhesion associated protein (FAAP), encoded by murine D10Wsu52e gene, is highly homologous to human HSPC117, which interacts with vinculin and talin. HeLa cells transfected with FAAP exhibited normal adhesion incorporation but showed impaired cell spreading, and restrained focal adhesion translocation. Moreover, FAAP facilitated vinculin-paxillin association, decreased interaction of paxillin-focal adhesion kinase and inhibited the phosphorylation of extracellular signal-regulated kinase. Together, these results suggest that FAAP, by virtue of modulating interaction of adhesion molecules, regulates cell adhesion dynamics.

The aim of this research was to evaluate the effect of dietary phytate on cardiovascular calcification in rats during aging. Male Wistar rats (10 weeks old) were randomly assigned to four diet groups. The control group was fed with a balanced diet (UAR-A04) containing phytate. The AIN group was fed a purified diet (AIN-76A) with an undetectable level of phytate. The PHY group was fed with a purified diet (AIN-76A) enriched with phytate (phytin, as the calcium magnesium salt). The MOD group was fed with the AIN-76A diet (phytate undetectable) enriched with MgO, inositol and CaHPO4. At 76 weeks of age all rats were sacrificed, and the aortas, hearts, kidneys, livers and femurs were removed for chemical analysis. The most significant differences were found in the aorta calcium content. Phytate-treated rats (the control and PHY groups) had significantly lower levels of calcium in the aorta compared to nonphytate-treated rats (AIN and MOD groups). The present study demonstrated that dietary phytate treatment significantly reduced age-related aorta calcification.

The enhanced activity of the cardiac Na+/H+ exchanger (NHE-1) after myocardial stretch is considered a key step of the intracellular signaling pathway leading to the slow force response to stretch as well as an early signal for the development of cardiac hypertrophy. We propose that the chain of events triggered by stretch begins with the release of small amounts of Angiotensin II (Ang II)/endothelin (ET) and ends with the increase in intracellular Ca2+ concentration ([Ca2+]i) through the Na+/Ca2+ exchanger in reverse mode (NCX(rev)), which triggers cardiac hypertrophy by activation of widely recognized Ca2+-dependent intracellular signaling pathways.