Impaired microbiota enzymatic activity observed in IBD-associated dysbiosis leads to modifications in the luminal BA pool composition. Altered BA transformation in the gut lumen can erase the anti-inflammatory effects of some BA species on gut epithelial cells and could participate in the chronic inflammation loop of IBD.

This study shows that stigmasterol inhibits several pro-inflammatory and matrix degradation mediators typically involved in OA-induced cartilage degradation, at least in part through the inhibition of the NF-kappaB pathway. These promising results justify further ex vivo and in vivo investigations with stigmasterol.

Lyso-phospholipids exert a major injurious effect on lung cell membranes during Acute Respiratory Distress Syndrome (ARDS), but the mechanisms leading to their in vivo generation are still unknown. Intratracheal administration of LPS to guinea pigs induced the secretion of type II secretory phospholipase A2 (sPLA2-II) accompanied by a marked increase in fatty acid and lyso-phosphatidylcholine (lyso-PC) levels in the bronchoalveolar lavage fluid (BALF). Administration of LY311727, a specific sPLA2-II inhibitor, reduced by 60% the mass of free fatty acid and lyso-PC content in BALF. Gas chromatography/mass spectrometry analysis revealed that palmitic acid and palmitoyl-2-lyso-PC were the predominant lipid derivatives released in BALF. A similar pattern was observed after the intratracheal administration of recombinant guinea pig (r-GP) sPLA2-II and was accompanied by a 50-60% loss of surfactant phospholipid content, suggesting that surfactant is a major lung target of sPLA2-II. In confirmation, r-GP sPLA2-II was able to hydrolyze surfactant phospholipids in vitro. This hydrolysis was inhibited by surfactant protein A (SP-A) through a direct and selective protein-protein interaction between SP-A and sPLA2-II. Hence, our study reports an in vivo direct causal relationship between sPLA2-II and early surfactant degradation and a new process of regulation for sPLA2-II activity. Anti-sPLA2-II strategy may represent a novel therapeutic approach in lung injury, such as ARDS. (

No abstract

A range of physiological processes has been imputed to lateral domain formation in biological membranes. However the molecular mechanisms of these functions and the details of how domain structures mediate these processes remain largely speculative. That domains exist in biomembranes and can be modeled in relatively simple lipid systems has contributed to our understanding of the principles governing phase behaviour in membranes. A presentation of these principles is the subject of this review. The condensing effect of sterols on phospholipids spread as monomolecular films at the air-water interface is described in terms of the dependence of the effect on sterol and phospholipid structure. The thermodynamics of sphingomyelin-cholesterol interactions are considered from calorimetric, densitometry and equilibrium cholesterol exchange measurements. Biophysical characterisation of the structure of liquid-ordered phase and its relationship with liquid-disordered phase is described from spectroscopic and X-ray scattering studies. Finally, the properties of liquid-ordered phase in the context of membrane physiology and permeability barrier properties are considered.

BackgroundBasic cell-penetrating peptides are potential vectors for therapeutic molecules and display antimicrobial activity. The peptide-membrane contact is the first step of the sequential processes leading to peptide internalization and cell activity. However, the molecular mechanisms involved in peptide-membrane interaction are not well understood and are frequently controversial. Herein, we compared the membrane activities of six basic peptides with different size, charge density and amphipaticity: Two cell-penetrating peptides (penetratin and R9), three amphipathic peptides and the neuromodulator substance P.Methodology/Principal FindingsExperiments of X ray diffraction, video-microscopy of giant vesicles, fluorescence spectroscopy, turbidimetry and calcein leakage from large vesicles are reported. Permeability and toxicity experiments were performed on cultured cells. The peptides showed differences in bilayer thickness perturbations, vesicles aggregation and local bending properties which form lipidic tubular structures. These structures invade the vesicle lumen in the absence of exogenous energy.Conclusions/SignificanceWe showed that the degree of membrane permeabilization with amphipathic peptides is dependent on both peptide size and hydrophobic nature of the residues. We propose a model for peptide-induced membrane perturbations that explains the differences in peptide membrane activities and suggests the existence of a facilitated “physical endocytosis,” which represents a new pathway for peptide cellular internalization.

No abstract

Thirty-four different loci for hereditary spastic paraplegias have been mapped, and 16 responsible genes have been identified. Autosomal recessive forms of spastic paraplegias usually have clinically complex phenotypes but the SPG5, SPG24 and SPG28 loci are considered to be associated with 'pure' forms of the disease. Very recently, five mutations in the CYP7B1 gene, encoding a cytochrome P450 oxysterol 7-alpha hydroxylase and expressed in brain and liver, have been found in SPG5 families. We analysed the coding region and exon-intron boundaries of the CYP7B1 gene by direct sequencing in a series of 82 unrelated autosomal recessive hereditary spastic paraplegia index patients, manifesting either a pure (n = 52) or a complex form (n = 30) of the disease, and in 90 unrelated index patients with sporadic pure hereditary spastic paraplegia. We identified eight, including six novel, mutations in CYP7B1 segregating in nine families. Three of these mutations were nonsense (p.R63X, p.R112X, p.Y275X) and five were missense mutations (p.T297A, p.R417H, p.R417C, p.F470I, p.R486C), the last four clustering in exon 6 at the C-terminal end of the protein. Residue R417 appeared as a mutational hot-spot. The mean age at onset in 16 patients was 16.4 +/- 12.1 years (range 4-47 years). After a mean disease duration of 28.3 +/- 13.4 years (10-58), spasticity and functional handicap were moderate to severe in all cases. Interestingly, hereditary spastic paraplegia was pure in seven SPG5 families but complex in two. In addition, white matter hyperintensities were observed on brain magnetic resonance imaging in three patients issued from two of the seven pure families. Lastly, the index case of one family had a chronic autoimmune hepatitis while his eldest brother died from cirrhosis and liver failure. Whether this association is fortuitous remains unsolved, however. The frequency of CYP7B1 mutations were 7.3% (n = 6/82) in our series of autosomal recessive hereditary spastic paraplegia families and 3.3% (n = 3/90) in our series of sporadic pure spastic paraplegia. The recent identification of CYP7B1 as the gene responsible for SPG5 highlights a novel molecular mechanism involved in hereditary spastic paraplegia determinism.