Influence of sarmesin on the cardiac and vascular actions of angiotensin II

Summary The angiotensin II (ANG II) receptor blocker properties of sarmesin and its influence on the homotropic cooperativity of ANG II receptors were studied in two experimental models: isolated rabbit aorta and isolated rabbit atria. The results show that: (i) sarmesin is a specific competitive antagonist of ANG II receptors, with high affinity (pA₂=8.93 in the isolated aorta and 8.66 in the isolated atria); and (ii) the slope of the concentration-response curves to ANG II and the Hill coefficient increased in the presence of sarmesin, the latter suggesting an enhancement of the positive homotropic cooperativity of ANG II receptors. These results may be explained overall by the reciprocal negative modulation of receptor affinity between sarmesin and ANG II, due, possibly, to opposite effects on the binding of G-proteins to ANG II receptors.     

Myeloid-derived growth factor regulates neutrophil motility in interstitial tissue damage

Neutrophil recruitment to tissue damage is essential for host defense but can also impede tissue repair. The cues that differentially regulate neutrophil responses to tissue damage and infection remain unclear. Here, we report that the paracrine factor myeloid-derived growth factor (MYDGF) is induced by tissue damage and regulates neutrophil motility to damaged, but not infected, tissues in zebrafish larvae. Depletion of MYDGF impairs wound healing, and this phenotype is rescued by depleting neutrophils. Live imaging and photoconversion reveal impaired neutrophil reverse migration and inflammation resolution in mydgf mutants. We found that persistent neutrophil inflammation in tissues of mydgf mutants was dependent on the HIF-1α pathway. Taken together, our data suggest that MYDGF is a damage signal that regulates neutrophil interstitial motility and inflammation through a HIF-1α pathway in response to tissue damage.     

Independent component analysis of Raman spectra: Application on paraffin-embedded skin biopsies

Raman spectra provide wealthy but complex information about the chemical constituents of biological samples. Digital processing techniques are usually needed to extract the spectra of chemical constituents and their associated concentration profiles. However, spectral signatures may admit transformations from those recorded on pure constituents and these techniques require a priori knowledge of spectra to be estimated. We propose in this study to analyse paraffin-embedded skin biopsies of malignant and benign tumors dedicated to oncology researches by Raman spectroscopy and advanced signal processing methods. We show that the commonly used principal component analysis (PCA) does not give physically interpretable estimators of spectra and associated concentration profiles. Based on a linear model and taking into account the statistical properties of spectra, independent component analysis (ICA) is used to better estimate the spectra of chemical constituents. The estimators of associated concentration profiles are no longer orthogonal and have only positive values, contrary to PCA. ICA allows to model the paraffin by three Raman spectra and provides good estimators of underlying spectra of the human skin, which is of great interest in oncology since the retrieval of spectral features of different types of skin tumors is sufficient for their discrimination.     

Syntaxin 6 and CAL Mediate the Degradation of the Cystic Fibrosis Transmembrane Conductance Regulator

The PDZ domain–containing protein CAL mediates lysosomal trafficking and degradation of CFTR. Here we demonstrate the involvement of a CAL-binding SNARE protein syntaxin 6 (STX6) in this process. Overexpression of STX6, which colocalizes and coimmunoprecipitates with CAL, dramatically reduces the steady-state level and stability of CFTR. Conversely, overexpression of a STX6 dominant-negative mutant increases CFTR. Silencing endogenous STX6 increases CFTR but has no effect on ΔTRL-CFTR, which cannot bind to CAL. Silencing CAL eliminates the effect of STX6 on CFTR. Both results suggest a dependence of CAL on STX6 function. Consistent with its Golgi localization, STX6 does not bind to ER-localized ΔF508-CFTR. Silencing STX6 has no effect on ΔF508-CFTR expression. However, overexpression of STX6 coimmunoprecipitates with and reduces temperature-rescued ΔF508-CFTR that escapes ER degradation. Conversely, silencing STX6 enhances the effect of low temperature in rescuing ΔF508-CFTR. Finally, in human bronchial epithelial cells, silencing endogenous STX6 leads to increases in protein levels and Cl⁻ currents of both wild-type and temperature-rescued CFTR. We have identified STX6 as a new component of the CAL complex that regulates the abundance and function of CFTR at the post-ER level. Our results suggest a therapeutic role of STX6 in enhancing rescued ΔF508-CFTR.     

Features of crossing-over in virus-infected tomato

The evidence of increased crossing over rate in tomato hybrids infected with TAV (Tomato aspermy virus), PVX (Potato virus X), TMV (Tobacco mosaic virus), TMV+PVX indicates the recombinogenic effect of viral infection. Cytological studies of the early diakinesis in healthy and virus-infected tomato revealed significant changes in chiasma number and position. The most significant changes were established for bivalents with two interstitial chiasmata and with one terminal and one interstitial. The data obtained indicate redistribution of the chiasmata position and induction of additional exchanges. The virus-induced recombination is segment-specific and depends on the host plant genotype, virus infection and the interaction between them.     

Polycystin-1 Negatively Regulates Polycystin-2 Expression via the Aggresome/Autophagosome Pathway

Mutations of the PKD1 and PKD2 genes, encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively, lead to autosomal dominant polycystic kidney disease. Interestingly, up-regulation or down-regulation of PKD1 or PKD2 leads to polycystic kidney disease in animal models, but their interrelations are not completely understood. We show here that full-length PC1 that interacts with PC2 via a C-terminal coiled-coil domain regulates PC2 expression in vivo and in vitro by down-regulating PC2 expression in a dose-dependent manner. Expression of the pathogenic mutant R4227X, which lacks the C-terminal coiled-coil domain, failed to down-regulate PC2 expression, suggesting that PC1-PC2 interaction is necessary for PC2 regulation. The proteasome and autophagy are two pathways that control protein degradation. Proteins that are not degraded by proteasomes precipitate in the cytoplasm and are transported via histone deacetylase 6 (HDAC6) toward the aggresomes. We found that HDAC6 binds to PC2 and that expression of full-length PC1 accelerates the transport of the HDAC6-PC2 complex toward aggresomes, whereas expression of the R4227X mutant fails to do so. Aggresomes are engulfed by autophagosomes, which then fuse with the lysosome for degradation; this process is also known as autophagy. We have now shown that PC1 overexpression leads to increased degradation of PC2 via autophagy. Interestingly, PC1 does not activate autophagy generally. Thus, we have now uncovered a new pathway suggesting that when PC1 is expressed, PC2 that is not bound to PC1 is directed to aggresomes and subsequently degraded via autophagy, a control mechanism that may play a role in autosomal dominant polycystic kidney disease pathogenesis.     

Collagen regulates the ability of endothelial progenitor cells to protect hypoxic myocardium through a mechanism involving miR‐377/VE‐PTP axis

The possibility to employ stem/progenitor cells in the cardiovascular remodelling after myocardial infarction is one of the main queries of regenerative medicine. To investigate whether endothelial progenitor cells (EPCs) participate in the restoration of hypoxia‐affected myocardium, we used a co‐culture model that allowed the intimate interaction between EPCs and myocardial slices, mimicking stem cell transplantation into the ischaemic heart. On this model, we showed that EPCs engrafted to some extent and only transiently survived into the host tissue, yet produced visible protective effects, in terms of angiogenesis and protection against apoptosis and identified miR‐377‐VE‐PTP axis as being involved in the protective effects of EPCs in hypoxic myocardium. We also showed that collagen, the main component of the myocardial scar, was important for these protective effects by preserving VE‐PTP levels, which were otherwise diminished by miR‐377. By this, a good face of the scar is revealed, which was so far perceived as having only detrimental impact on the exogenously delivered stem/progenitor cells by affecting not only the engraftment, but also the general protective effects of stem cells.     

Molecular processes in the streptokinase thrombolytic therapy

The aim of this research is to evaluate the current streptokinase thrombolytic treatment and to identify or improve new techniques that will base new approaches with a higher efficiency in this area of expertise. In order to be as realistic as possible a new method was set up using magnetic vectorized nanoparticles streptokinase and human blood thrombus. The experimental data confirm the maximum 83% thrombus lyses whenever increase streptokinase concentration. It is very probable to happen because of the presence of high concentration of antiplasmin in the blood that neutralizes around half of the thrombolytic potential of the sanguine plasminogen. The experiment shows also that only free serum plasminogen are available for streptokinase action in order to generate plasmin.     

Gamma-glutamyltransferase,possible novel biomarker in colon diverticulosis: a case-control study

The gamma-glutamyltransferase (GGT) is recognized in medical practice as a useful indicator for the detection of liver lesions, especially those induced by the excessive consumption of alcoholic or cholesterol-associated drinks. The present study, although it includes a very small number of cases diagnosed with colon diverticulosis-diverticulitis associated with polyposis at the same intestinal level, identifies the presence of increased circulating concentrations of this enzyme in the serum. Its serum levels are tracked “dynamically” throughout a year after the diagnosis and start of the therapy. The study calls into question the release of the enzyme from the edge of the enterocytes’ brush-like edge, leading to the pathogenic disturbance of regional redox homeostasis. The hypothesis gives the circulating values of GGT predictive value for cellular oxidative stress, as well as for indirectly expressing the glutathione level in cytosol.