Les traitements non médicamenteux de la constipation pour augmenter la qualité de vie en EMS: revue de littérature

La constipation touche la majorité des résidents vivant en établissement médico-social. Le traitement principal pour cette affection est l’administration de laxatif. Pourtant ce traitement ne présente pas le résultat escompté. D’autres moyens alternatifs doivent être mis en place pour traiter la constipation fonctionnelle et ainsi améliorer la qualité de vie et le bien-être

Beta-amyloid-acetylcholine structural interaction: evidence for neuroprotective effects of acetylcholine in neural cells

Alzheimer’s disease (AD) is regarded as a multifactorial disease characterized by a complex pathogenesis including a cholinergic deficit - due to degeneration of cholinergic projections from the basal forebrain - and the extracellular accumulation of amyloid beta (Aβ) peptide. Aβ containing 39 to 42 amino acids is the predominant component of the senile plaques that, together with neurofibrillary tangles, are regarded as the neuropathological hallmarks of AD (Sorrentino et al. 2014). Aβ may assume different conformations changing from random coil or α-helical monomers to β-sheet structures forming toxic oligomers and/or β-sheet mature fibrils. In this framework, we studied the effect of acetylcholine (ACh) on the conformation of Aβ by circular dichroism analysis. Moreover we investigated the ability of ACh to protect neuronal cells from the toxic action of amyloid peptide and to modulate the neuroinflammatory response occurring via the phospholipase A2 (PLA2). Results show that the amount of Aβ(25-35) β-strand raised linearly in absence of ACh, whereas it remained almost constant in presence of ACh. In addition, in a micelle solution mimicking the membrane environment ACh was found effective in increasing and stabilizing the soluble and not toxic helical content of Aβ(25-35) suggesting that ACh is capable to preserve the soluble form of Aβ(25-35), reducing the incipit of Aβ aggregation. In order to assess the neuro-protective ability of ACh against toxic Aβ(25-35) accumulation, we used neural cell (NCC) cultures containing both astrocytes and glial cells prepared from brains embryos from timed pregnant Wistar rats and infused ACh for 48h. By immunostaining, we observed that ACh reduced Aβ(25-35)-induced cell death. Then, we tested the protective effect of ACh on inflammation induced by Aβ administration. NCC were challenged with Aβ(25-35) in the presence and absence of ACh and immunostained for astroglial and neuronal markers: results showed a reduction of the morphological features of astrogliosys in ACh treated cells. PLA2 expression analysis corroborated these data also underlying that ACh can negatively regulate inflammation pathways in glial cells

1,4-Disubstituted-[1,2,3]triazolyl-Containing Analogues of MT-II: Design, Synthesis, Conformational Analysis, and Biological Activity

Side chain-to-side chain cyclizations represent a strategy to select a family of bioactive conformations by reducing the entropy and enhancing the stabilization of functional ligand-induced receptor conformations. This structural manipulation contributes to increased target specificity, enhanced biological potency, improved pharmacokinetic properties, increased functional potency, and lowered metabolic susceptibility. The CuI-catalyzed azide–alkyne 1,3-dipolar Huisgen’s cycloaddition, the prototypic click reaction, presents a promising opportunity to develop a new paradigm for an orthogonal bioorganic and intramolecular side chain-to-side chain cyclization. In fact, the proteolytic stable 1,4- or 4,1-disubstituted [1,2,3]triazolyl moiety is isosteric with the peptide bond and can function as a surrogate of the classical side chain-to-side chain lactam forming bridge. Herein we report the design, synthesis, conformational analysis, and functional biological activity of a series of i-to-i+5 1,4- and 4,1-disubstituted [1,2,3]triazole-bridged cyclopeptides derived from MT-II, the homodetic Asp5 to Lys10 side chain-to-side chain bridged heptapeptide, an extensively studied agonist of melanocortin receptors

Stacking Interactions between Adenines in Oxidized Oligonucleotides

The effects of stacking interactions on the oxidation potentials of single strand oligonucleotides containing up to four consecutive adenines, alternated with thymines and cytosines in different sequences and ratios, have been determined by means of differential pulse voltammetry. Voltammetric measurements point toward the establishment in solution of structured oligonucleotide conformations, in which the nucleobases are well stacked altogether. Molecular dynamics simulations confirm that finding, indicating that single strands assume geometrical parameters characteristic of the B-DNA form. The analysis of the voltammetric signals in terms of a simple effective tight binding quantum model leads one to infer a robust set of parameters for treating hole transfer in one-electron-oxidized DNA containing adenines and thymines

The glycan role in the glycopeptide immunogenicity revealed by atomistic simulations and spectroscopic experiments on the multiple sclerosis biomarker CSF114(Glc)

Glycoproteins are often recognized as not-self molecules by antibodies triggering the onset of severe autoimmune diseases such as Multiple Sclerosis (MS). Thus, the development of antigen-mimicking biomarkers represents an attractive strategy for an early diagnosis of the disease. An example is the synthetic glycopeptide CSF114(Glc), which was designed and tested as MS biomarker and whose clinical application was limited by its reduced ability to detect autoantibodies in MS patients. In the attempt to improve the efficacy of CSF114(Glc), we have characterized all the events leading to the final binding of the biomarker to the autoantibody using atomistic simulations, ESR and NMR experiments. The glycosydic moiety plays a primary role in the whole process. In particular, in an environment mimicking that used in the clinical tests the glycopeptide assumes a a-helix structure that is functional for the interaction with the antibody. In this conformation CSF114(Glc) binds the monoclonal antibody mAb8-18C5 similarly to the myelin oligodendrocyte glycoprotein MOG, which is a known MS auto-antigen, thus explaining its diagnostic activity. Our study offers new molecular bases to design more effective biomarkers and provides a most valid protocol to investigate other systems where the environment effect is determinant for the biological activit

Alterations of Mitochondrial Respiration and Complex I Activity in Mononucleate Cells from Psoriatic Patients: Possible Involvement of GRIM-19-STAT3α/β

Objective: Although the pathogenesis of psoriasis is largely unknown accumulating evidences configure it as an immune-mediated disease determined through cytokines-mediated positive loops between activated lymphocytes subsets and keratinocytes. Mitochondria in addition to their role in the cell bioenergetics are now recognized as a decisional hub in controlling the immunological response. In the present study we compared mitochondria-related functions of PBMC between psoriatic patients and healthy controls. Methods: Freshly isolated PBMC from eleven psoriatic patients and nine healthy controls were subjected to mitochondria-dependent respiratory activity measurements by high-resolution oxymetry and the specific activity of respiratory chain complexes assessed by spectrophotometric assays. Quantitative RT-PCR and immunoblotting were applied to detect the level of selected transcripts and proteins respectively. Results: Respirometric analysis unveiled in patients’ cells a significant three-fold increase of oligomycin- sensitive endogenous mitochondria-driven oxygen consumption, which was traceable back to a specific increased activity of the respiratory chain complex I. Analysis by quantitative RT-PCR of transcription factors regulating the mitochondrial biogenesis did not result in significant changes between patients and control cells and was confirmed by the unaffected expression of the complex I subunits. Treatment of either patients’ or control cells with isoproterenol and IBMX ruled out the involvement of a cAMP-PKA-mediated post-transcriptional modification of the respiratory complex. GRIM19 a pleiotropic protein, involved in the structural and functional stabilization of complex I and in the mitochondrial translocation of STAT3 was significantly up-regulated in patients’ cells. Phosphorylation at S727 of STAT3 was increased in patients’cells, which, in addition, unveiled a shift in the relative expression of the STAT3α/β splisoforms. Conclusion: Altogether the results obtained suggest the occurrence in circulating mononucleate cells from psoriatic patients of an altered activity of complex I likely mediated by up-regulation of GRIM19/STAT3β, which might lead to a chronic activation of T-lymphocytes thereby contributing to the development of psoriasis

A serum nuclear magnetic resonance-based metabolomic signature of antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a rheumatic inflammatory chronic autoimmune disease inducing hypercoagulable state associated with vascular thrombosis and pregnancy loss in women. Cardiac, cerebral and vascular strokes in these patients are responsible for reduction in life expectancy. Timely diagnosis and accurate monitoring of disease are decisive to improve the accuracy of therapy. In the present work, we present a NMR-based metabolomic study of blood sera of APS patients. Our data show that individuals suffering APS have a characteristic metabolomic profile with abnormalities associated to the metabolism of methyl group donors, ketone bodies and amino acids. We have identified for the first time the metabolomic fingerprint characterizing APS disease having potential application to improve APS timely diagnosis and appropriate therapeutic approaches

Binding of the hemopressin peptide to the cannabinoid CB(1) receptor: structural insights

Hemopressin, a bioactive nonapeptide derived from the α1 chain of hemoglobin, was recently shown to possess selective antagonist activity at the cannabinoid CB(1) receptor [Heimann, A. S., et al. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 20588-20593]. CB(1) receptor antagonists have been extensively studied for their possible therapeutic use in the treatment of obesity, drug abuse, and heroin addiction. In particular, many compounds acting as CB(1) receptor antagonists have been synthesized and subjected to experiments as possible anti-obesity drugs, but their therapeutic application is still complicated by important side effects. Using circular dichroism and nuclear magnetic resonance spectroscopy, this work reports the conformational analysis of hemopressin and its truncated, biologically active fragment hemopressin(1-6). The binding modes of both hemopressin and hemopressin(1-6) are investigated by molecular docking calculations. Our conformational data indicate that regular turn structures in the central portion of hemopressin and hemopressin(1-6) are critical for an effective interaction with the receptor. The results of molecular docking calculations, indicating similarities and differences in comparison to the most accepted CB(1) pharmacophore model, suggest the possibility of new chemical scaffolds for the design of new CB(1) antagonist lead compounds