Ursodeoxycholic Acid Binds PERK and Ameliorates Neurite Atrophy in a Cellular Model of GM2 Gangliosidosis.

The Unfolded protein response (UPR), triggered by stress in the endoplasmic reticulum (ER), is a key driver of neurodegenerative diseases. GM2 gangliosidosis, which includes Tay-Sachs and Sandhoff disease, is caused by an accumulation of GM2, mainly in the brain, that leads to progressive neurodegeneration. Previously, we demonstrated in a cellular model of GM2 gangliosidosis that PERK, a UPR sensor, contributes to neuronal death.

Efficacy of topical risedronate and risedronate - Eudragit E complex in a model of cutaneous leishmaniasis induced by .

An efficacious topical treatment for cutaneous leishmaniasis (CL) is highly desirable but still an ongoing challenge. Systemic risedronate (Ris) has been reported to have anti-leishmanial properties and Eudragit EPO (EuE) has shown activity against . The aim of this work was to investigate the efficacy of topical Ris and EuE-Ris complexes on CL.

Efficacy of topical Miltefosine formulations in an experimental model of cutaneous leishmaniasis.

Cutaneous leishmaniasis (CL) is a neglected tropical disease endemic in ~ 90 countries, with an increasing incidence. Presently available pharmacotherapy implies the systemic administration of moderately/very toxic drugs. Miltefosine (Milt) is the only FDA-approved drug to treat CL via the oral route (Impavido®).

Effect of Anti-Leishmania Drugs on the Structural and Elastic Properties of Ultradeformable Lipid Membranes.

Drugs for treating Leishmaniasis, a parasitic tropical orphan disease, currently have several limitations on their use, which topical treatments could alleviate. Topical treatment requires penetration of drugs deep into the skin, which is aided by encapsulation within ultradeformable liposomes. Penetrability depends on the flexibility of the lipid membrane, which may be affected by the drugs.

Early activation of CD95 is limited and localized to the cytotoxic synapse.

The cytotoxic synapse formed between cytotoxic T lymphocytes or natural killer cells expressing CD95L and target cells with CD95 on their surface is a key pathway for apoptosis induction by the immune system. Despite similarities with the immune synapse in antigen presenting cells, little is known about the role of the spatiotemporal organization of agonistic proteins/receptor interactions for CD95 signaling. Here, we have developed an artificial cytotoxic synapse to examine how mobility and geometry of an anti-CD95 agonistic antibody affect receptor aggregation and mobility, ie the first step of receptor activation.

Agonist mobility on supported lipid bilayers affects Fas mediated death response.

Extrinsic apoptosis is initiated by recognition and clustering of the single-pass transmembrane proteins Fas ligand and Fas expressed at the surface of closely apposed lymphocytes and target cells, respectively. Since Fas-mediated death response was mainly studied with soluble antibodies, the mobility constraints for receptor activation by a membrane embedded agonist is not well understood. We explored this influence by stimulating apoptosis on functionalized supported lipid bilayers, where we quantified agonist mobility by z-scan fluorescence correlation spectroscopy.

One-Photon Lithography for High-Quality Lipid Bilayer Micropatterns.

A relevant question in cell biology with broad implications in biomedicine is how the organization and dynamics of interacting membranes modulate signaling cascades that involve cell-cell contact. The functionalization of surfaces with supported lipid bilayers containing tethered proteins is a particularly useful method to present ligands with membrane-like mobility to cells. Here, we present a method to generate micrometer-sized patches of lipid bilayers decorated with proteins.

Structural features of ultradeformable archaeosomes for topical delivery of ovalbumin.

The ultradeformable archaeosomes (UDA, made of total polar archaeolipids (TPA) extracted from the extreme halophile archaea Halorubrum tebenquichense:soybean phosphatidylcholine (SPC):sodium cholate (NaChol), 3:3:1 w:w), are promising topical adjuvants showing high deformability, an essential property for intact skin penetration up to the viable epidermis/dermis. To gain insights on UDA structure, the interactions between TPA, SPC and the edge activator NaChol, were assessed by electrospray ionization mass spectroscopy (ESI-MS) and confocal fluorescence microscopy of giant unilamellar vesicles (GUV). The non covalent heterodimers NaChol-SPC, NaChol-phosphatidylglycerophosphate methyl ether (PGPMe), NaChol-sulfated diglycosyl diphytanyl-glycerol diether (SDGD5) and SPC-PGPMe detected in the gas phase by ESI-MS after direct infusion of UDA, together with the homogeneous partition of FASTDiO and DiIC18 in GUV suggested that in these proportions, lipids and NaChol were miscible.

Fluorescence correlation spectroscopy for the study of membrane dynamics and organization in giant unilamellar vesicles.

Fluorescence correlation spectroscopy (FCS) is a powerful technique to study the lateral organization of membranes. It measures fluorescence intensity fluctuations in the single molecule regime and allows the determination of diffusion coefficients. When applied to lipid membranes, their fluidity and lipid phase can be estimated from the diffusion rates of fluorescent particles partitioned to the membrane.

Pig skin structure and transdermal delivery of liposomes: a two photon microscopy study.

In this work we have characterized the architecture and physical properties of pig skin epidermis including its permeability to different liposome formulations. Autofluorescence images show that cells in the epidermis, from the basal layer to the stratum corneum, are organized in clusters that are in turn separated by particular structures we named "canyons". These canyons start in the surface as a wrinkle, eventually closing and going all the way inside the epidermis as a distinct structure that reaches the stratum basale.

Membrane domain-disrupting effects of 4-substitued cholesterol derivatives.

A wide range of cellular functions are thought to be regulated not only by the activity of membrane proteins, but also by the local membrane organization, including domains of specific lipid composition. Thus, molecules and drugs targeting and disrupting this lipid pattern, particularly of the plasma membrane, will not only help to investigate the role of membrane domains in cell biology, but might also be interesting candidates for therapy. We have identified three 4-substituted cholesterol derivatives that are able to induce a domain-disrupting effect in model membranes.

Effects of a short-chain ceramide on bilayer domain formation, thickness, and chain mobililty: DMPC and asymmetric ceramide mixtures.

An important part of natural ceramides contain asymmetric hydrocarbon chains. We have used calorimetry, atomic force microscopy, and electron paramagnetic resonance to study the effect of ceramide chain asymmetry in mixtures of C8Cer with DMPC as a model system of hydrocarbon chain disparity. A phase diagram is provided along with information on the thickness of the membrane and the mobility of the chains at different temperatures both below and above the phase transition temperature of the mixtures.

Ceramide modulates the lipid membrane organization at molecular and supramolecular levels.

The role of lipids in membranes has changed rapidly from static to dynamic and emphasized their involvement in information transduction, linking temporal and topological structuring through compositionally driven effects. Ceramide has been described as an important modulator of different membrane functions. In mixtures with ganglioside GM1, the condensation induced by ceramide increases intermolecular interactions, leading to an increase of the phase transition temperature and size of the self-assembled structure.