Trefoil Factor 3 (TFF3) Is Regulated by Food Intake,Improves Glucose Tolerance and Induces Mucinous Metaplasia

Trefoil factor 3 (TFF3), also called intestinal trefoil factor or Itf, is a 59 amino acid peptide found as a homodimer predominantly along the gastrointestinal tract and in serum. TFF3 expression is elevated during gastrointestinal adenoma progression and has been shown to promote mucosal wound healing. Here we show that in contrast to other trefoil factor family members, TFF1 and TFF2, TFF3 is highly expressed in mouse duodenum, jejunum and ileum and that its expression is regulated by food intake. Overexpression of TFF3 using a recombinant adeno-associated virus (AAV) vector, or daily administration of recombinant TFF3 protein in vivo improved glucose tolerance in a diet-induced obesity mouse model. Body weight, fasting insulin, triglyceride, cholesterol and leptin levels were not affected by TFF3 treatment. Induction of mucinous metaplasia was observed in mice with AAV-mediated TFF3 overexpression, however, no such adverse histological effect was seen after the administration of recombinant TFF3 protein. Altogether these results suggest that the therapeutic potential of targeting TFF3 to treat T2D may be limited.     

Impact of Alginate Composition: From Bead Mechanical Properties to Encapsulated HepG2/C3A Cell Activities for In Vivo Implantation

Recently, interest has focused on hepatocytes’ implantation to provide end stage liver failure patients with a temporary support until spontaneous recovery or a suitable donor becomes available. To avoid cell damage and use of an immunosuppressive treatment, hepatic cells could be implanted after encapsulation in a porous biomaterial of bead or capsule shape. The aim of this study was to compare the production and the physical properties of the beads, together with some hepatic cell functions, resulting from the use of different material combinations for cell microencapsulation: alginate alone or combined with type I collagen with or without poly-L-lysine and alginate coatings. Collagen and poly-L-lysine increased the bead mechanical resistance but lowered the mass transfer kinetics of vitamin B12. Proliferation of encapsulated HepG2/C3A cells was shown to be improved in alginate-collagen beads. Finally, when the beads were subcutaneously implanted in mice, the inflammatory response was reduced in the case of alginate mixed with collagen. This in vitro and in vivo study clearly outlines, based on a systematic comparison, the necessity of compromising between material physical properties (mechanical stability and porosity) and cell behavior (viability, proliferation, functionalities) to define optima hepatic cell microencapsulation conditions before implantation.     

Blockade of vascular endothelial growth factor receptor I (VEGF-RI), but not VEGF-RII, suppresses joint destruction in the K/BxN model of rheumatoid arthritis

It was recently shown that vascular endothelial growth factor (VEGF), a growth factor for endothelial cells, plays a pivotal role in rheumatoid arthritis. VEGF binds to specific receptors, known as VEGF-RI and VEGF-RII. We assessed the physical and histological effects of selective blockade of VEGF and its receptors in transgenic K/BxN mice, a model of rheumatoid arthritis very close to the human disease. Mice were treated with anti-mouse VEGF Ab, anti-mouse VEGF-RI and -RII Abs, and an inhibitor of VEGF-RI tyrosine kinase. Disease activity was monitored using clinical indexes and by histological examination. We found that synovial cells from arthritic joints express VEGF, VEGF-RI, and VEGF-RII. Treatment with anti-VEGF-RI strongly attenuated the disease throughout the study period, while anti-VEGF only transiently delayed disease onset. Treatment with anti-VEGF-RII had no effect. Anti-VEGF-RI reduced the intensity of clinical manifestations and, based on qualitative and semiquantitative histological analyses, prevented joint damage. Treatment with a VEGF-RI tyrosine kinase inhibitor almost abolished the disease. These results show that VEGF is a key factor in pannus development, acting through the VEGF-RI pathway. The observation that in vivo administration of specific inhibitors targeting the VEGF-RI pathway suppressed arthritis and prevented bone destruction opens up new possibilities for the treatment of rheumatoid arthritis.     

Difference in plasticity of resting metabolic rate – the proximate explanation to different niche breadth in sympatric Ficedula flycatchers

Variation in relative fitness of competing recently formed species across heterogeneous environments promotes coexistence. However, the physiological traits mediating such variation in relative fitness have rarely been identified. Resting metabolic rate (RMR) is tightly associated with life history strategies, thermoregulation, diet use, and inhabited latitude and could therefore moderate differences in fitness responses to fluctuations in local environments, particularly when species have adapted to different climates in allopatry. We work in a long‐term study of collared (Ficedula albicollis) and pied flycatchers (Ficedula hypoleuca) in a recent hybrid zone located on the Swedish island of Öland in the Baltic Sea. Here, we explore whether differences in RMR match changes in relative performance of growing flycatcher nestlings across environmental conditions using an experimental approach. The fitness of pied flycatchers has previously been shown to be less sensitive to the mismatch between the peak in food abundance and nestling growth among late breeders. Here, we find that pied flycatcher nestlings have lower RMR in response to higher ambient temperatures (associated with low food availability). We also find that experimentally relaxed nestling competition is associated with an increased RMR in this species. In contrast, collared flycatcher nestlings did not vary their RMR in response to these environmental factors. Our results suggest that a more flexible nestling RMR in pied flycatchers is responsible for the better adaptation of pied flycatchers to the typical seasonal changes in food availability experienced in this hybrid zone. Generally, subtle physiological differences that have evolved when species were in allopatry may play an important role to patterns of competition, coexistence, or displacements between closely related species in secondary contact.     

Migration patterns of Hoopoe Upupa epops and Wryneck Jynx torquilla: an analysis of European ring recoveries

For many bird species, recovery of ringed individuals remains the best source of information about their migrations. In this study, we analyzed the recoveries of ringed European Hoopoe (Upupa epops) and the Eurasian Wryneck (Jynx torquilla) from 1914 to 2005 from all European ringing schemes. The aim was to define general migration directions and to make inferences about the winter quarters, knowing that hardly any recoveries are available from sub-Saharan Africa. For the autumn migration, there is evidence of a migratory divide for the Hoopoe in Central Europe, at approximately 10–12°E. Autumn migration directions of Wrynecks gradually change from SW to SE depending on the longitude (west to east) of the ringing place. In both species, only a few recoveries were available indicating spring migration directions, but they showed similar migration axes as for autumn migration, and hence no evidence for loop-migration. Due to a paucity of recoveries on the African continent, we can make only limited inferences about wintering grounds: extrapolating migration directions are only indicative of the longitude of the wintering area. The directions of autumn migration indicate a typical pattern observed in European long-distance migrants: west-European Hoopoes and Wrynecks are likely to winter in western Africa, while central- and east-European birds probably winter more in the east. Due to the migratory divide, for the Hoopoe, this phenomenon is more pronounced.     

Fitting yeast and mammalian prion aggregation kinetic data with the Finke-Watzky two-step model of nucleation and autocatalytic growth

Recently, we reported 14 amyloid protein aggregation kinetic data sets that were fit using the "Ockham's razor"/minimalistic Finke-Watzky (F-W) two-step model of slow nucleation (A --> B, rate constant k 1) and fast autocatalytic growth (A + B --> 2B, rate constant k 2), yielding quantitative (average) rate constants for nucleation ( k 1) and growth ( k 2), where A is the monomeric protein and B is the polymeric protein [Morris, A. M., et al. (2008) Biochemistry 47, 2413-2427]. Herein, we apply the F-W model to 27 representative prion aggregation kinetic data sets obtained from the literature. Each prion data set was successfully fit with the F-W model, including three different yeast prion proteins (Sup35p, Ure2p, and Rnq1p) as well as mouse and human prions. These fits yield the first quantitative rate constants for the steps of nucleation and growth in prion aggregation. Examination of a Sup35p system shows that the same rate constants are obtained for nucleation and for growth within experimental error, regardless of which of six physical methods was used, a unique set of important control experiments in the protein aggregation literature. Also provided herein are analyses of several factors influencing the aggregation of prions such as glutamine/asparagine rich regions and the number of oligopeptide repeats in the prion domain. Where possible, verification or refutation of previous correlations to glutamine/asparagine regions, or the number of repeat sequences, in literature aggregation kinetics is given in light of the quantitative rate constants obtained herein for nucleation and growth during prion aggregation. The F-W model is then contrasted to four literature mechanisms that address the molecular picture of prion transmission and propagation. Key limitations of the F-W model are listed to prevent overinterpretation of the data being analyzed, limitations that derive ultimately from the model's simplicity. Finally, possible avenues of future research are suggested.     

Co-receptor requirements for fibroblast growth factor-19 signaling

FGF19 is a unique member of the fibroblast growth factor (FGF) family of secreted proteins that regulates bile acid homeostasis and metabolic state in an endocrine fashion. Here we investigate the cell surface receptors required for signaling by FGF19. We show that betaKlotho, a single-pass transmembrane protein highly expressed in liver and fat, induced ERK1/2 phosphorylation in response to FGF19 treatment and significantly increased the interactions between FGF19 and FGFR4. Interestingly, our results show that alphaKlotho, another Klotho family protein related to betaKlotho, also induced ERK1/2 phosphorylation in response to FGF19 treatment and increased FGF19-FGFR4 interactions in vitro, similar to the effects of betaKlotho. In addition, heparin further enhanced the effects of both alphaKlotho and betaKlotho in FGF19 signaling and interaction experiments. These results suggest that a functional FGF19 receptor may consist of FGF receptor (FGFR) and heparan sulfate complexed with either alphaKlotho or betaKlotho.     

IL-26 Is Overexpressed in Rheumatoid Arthritis and Induces Proinflammatory Cytokine Production and Th17 Cell Generation

Interleukin-26 (IL-26), a member of the IL-10 cytokine family, induces the production of proinflammatory cytokines by epithelial cells. IL-26 has been also reported overexpressed in Crohn''s disease, suggesting that it may be involved in the physiopathology of chronic inflammatory disorders. Here, we have analyzed the expression and role of IL-26 in rheumatoid arthritis (RA), a chronic inflammatory disorder characterized by joint synovial inflammation. We report that the concentrations of IL-26 are higher in the serums of RA patients than of healthy subjects and dramatically elevated in RA synovial fluids compared to RA serums. Immunohistochemistry reveals that synoviolin⁺ fibroblast-like synoviocytes and CD68⁺ macrophage-like synoviocytes are the main IL-26-producing cells in RA joints. Fibroblast-like synoviocytes from RA patients constitutively produce IL-26 and this production is upregulated by IL-1-beta and IL-17A. We have therefore investigated the role of IL-26 in the inflammatory process. Results show that IL-26 induces the production of the proinflammatory cytokines IL-1-beta, IL-6, and tumor necrosis factor (TNF)-alpha by human monocytes and also upregulates the expression of numerous chemokines (mainly CCL20). Interestingly, IL-26-stimulated monocytes selectively promote the generation of RORgamma t⁺ Th17 cells, through IL-1-beta secretion by monocytes. More precisely, IL-26-stimulated monocytes switch non-Th17 committed (IL-23R⁻ or CCR6⁻ CD161⁻) CD4⁺ memory T cells into Th17 cells. Finally, synovial fluids from RA patients also induce Th17 cell generation and this effect is reduced after IL-26 depletion. These findings show that IL-26 is constitutively produced by RA synoviocytes, induces proinflammatory cytokine secretion by myeloid cells, and favors Th17 cell generation. IL-26 thereby appears as a novel proinflammatory cytokine, located upstream of the proinflammatory cascade, that may constitute a promising target to treat RA and chronic inflammatory disorders.     

Aldolase predicts subsequent myopathy occurrence in systemic sclerosis

Introduction

Myopathy related to systemic sclerosis (Myo-SSc) is a disabling and unpredictable complication of SSc. We assessed the predictive value of serum aldolase, creatine kinase (CK), alanine transaminase (ALT), aspartate transaminase (AST) and C-reactive protein (CRP) to estimate the risk of developing Myo-SSc.

Methods

We enrolled 137 SSc patients without proximal muscle weakness in a prospective monocentric study to follow them longitudinally over a four-year period. The risk of occurrence of Myo-SSc was ascertained according to the European NeuroMuscular Centre criteria and was analyzed according to levels of plasma aldolase, CK, transaminase enzymes and CRP at inclusion. Performance of each parameter to predict Myo-SSc occurrence was assessed and compared with the others.

Results

The area under the receiver operating characteristic curves (ROC) of plasma aldolase for Myo-SSc occurrence prediction was 0.80 (95% CI: 0.67 to 0.94, P < 0.001), which was higher than that of plasma CK (0.75, P = 0.01), and that of ALT (0.63, P = 0.04). AST and CRP had no predictive value for Myo-SSc occurrence. The best cut-off of aldolase for prediction of Myo-SSc occurrence within three years after inclusion was 9 U/L and higher than the upper normality limit (7 U/L), unlike that of CK and ALT. Myo-SSc occurred more frequently in patients whose plasma aldolase was higher than 9 U/L. Adjusted Hazard Ratio for patients with aldolase > 9 U/L was 10.3 (95% CI: 2.3 to 45.5), P < 0.001.

Conclusions

Increased plasma aldolase level accurately identified SSc patients with high risk to develop subsequent Myo-SSc. This could help initiate appropriate treatment when the disabling muscle damage is still in a reversible stage.