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1.
Pharmaceutics ; 16(4)2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38675209

ABSTRACT

Small RNA molecules such as microRNA and small interfering RNA (siRNA) have become promising therapeutic agents because of their specificity and their potential to modulate gene expression. Any gene of interest can be potentially up- or down-regulated, making RNA-based technology the healthcare breakthrough of our era. However, the functional and specific delivery of siRNAs into tissues of interest and into the cytosol of target cells remains highly challenging, mainly due to the lack of efficient and selective delivery systems. Among the variety of carriers for siRNA delivery, peptides have become essential candidates because of their high selectivity, stability, and conjugation versatility. Here, we describe the development of molecules encompassing siRNAs against SOD1, conjugated to peptides that target the low-density lipoprotein receptor (LDLR), and their biological evaluation both in vitro and in vivo.

2.
Cell Rep ; 37(5): 109914, 2021 11 02.
Article in English | MEDLINE | ID: mdl-34731626

ABSTRACT

A variety of mechanosensory neurons are involved in touch, proprioception, and pain. Many molecular components of the mechanotransduction machinery subserving these sensory modalities remain to be discovered. Here, we combine recordings of mechanosensitive (MS) currents in mechanosensory neurons with single-cell RNA sequencing. Transcriptional profiles are mapped onto previously identified sensory neuron types to identify cell-type correlates between datasets. Correlation of current signatures with single-cell transcriptomes provides a one-to-one correspondence between mechanoelectric properties and transcriptomically defined neuronal populations. Moreover, a gene-expression differential comparison provides a set of candidate genes for mechanotransduction complexes. Piezo2 is expectedly found to be enriched in rapidly adapting MS current-expressing neurons, whereas Tmem120a and Tmem150c, thought to mediate slow-type MS currents, are uniformly expressed in all mechanosensory neuron subtypes. Further knockdown experiments disqualify them as mediating MS currents in sensory neurons. This dataset constitutes an open resource to explore further the cell-type-specific determinants of mechanosensory properties.


Subject(s)
Ganglia, Spinal/metabolism , Gene Expression Profiling , Mechanotransduction, Cellular/genetics , Neurons/metabolism , Transcriptome , Animals , Ganglia, Spinal/cytology , Gene Expression Regulation , HEK293 Cells , Humans , Ion Channels/genetics , Ion Channels/metabolism , Male , Membrane Potentials , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , NIH 3T3 Cells , Patch-Clamp Techniques , RNA-Seq , Single-Cell Analysis
3.
Sci Rep ; 9(1): 9183, 2019 06 24.
Article in English | MEDLINE | ID: mdl-31235716

ABSTRACT

The blood-brain barrier (BBB) regulates the traffic of molecules into the central nervous system (CNS) and also limits the drug delivery. Due to their flexible properties, liposomes are an attractive tool to deliver drugs across the BBB. We previously characterized gH625, a peptide derived from Herpes simplex virus 1. The present study investigates the efficiency of liposomes functionalized on their surface with gH625 to promote the brain uptake of neuroprotective peptide PACAP (pituitary adenylate cyclase-activating polypeptide). Using a rat in vitro BBB model, we showed that the liposomes preparations were non-toxic for the endothelial cells, as assessed by analysis of tight junction protein ZO1 organization and barrier integrity. Next, we found that gH625 improves the transfer of liposomes across endothelial cell monolayers, resulting in both low cellular uptake and increased transport of PACAP. Finally, in vivo results demonstrated that gH625 ameliorates the efficiency of liposomes to deliver PACAP to the mouse brain after intravenous administration. gH625-liposomes improve both PACAP reaching and crossing the BBB, as showed by the higher number of brain cells labelled with PACAP. gH625-liposomes represent a promising strategy to deliver therapeutic agents to CNS and to provide an effective imaging and diagnostic tool for the brain.


Subject(s)
Blood-Brain Barrier/drug effects , Drug Delivery Systems , Liposomes/pharmacokinetics , Peptides/pharmacokinetics , Pituitary Adenylate Cyclase-Activating Polypeptide/pharmacokinetics , Viral Envelope Proteins/pharmacokinetics , Administration, Intravenous , Animals , Biological Transport , Cells, Cultured , Endothelial Cells/cytology , Endothelial Cells/metabolism , Mice , Pituitary Adenylate Cyclase-Activating Polypeptide/administration & dosage , Rats , Rats, Wistar
4.
Nat Commun ; 6: 7223, 2015 May 26.
Article in English | MEDLINE | ID: mdl-26008989

ABSTRACT

Piezo1 and Piezo2 encode mechanically activated cation channels that function as mechanotransducers involved in vascular system development and touch sensing, respectively. Structural features of Piezos remain unknown. Mouse Piezo1 is bioinformatically predicted to have 30-40 transmembrane (TM) domains. Here, we find that nine of the putative inter-transmembrane regions are accessible from the extracellular side. We use chimeras between mPiezo1 and dPiezo to show that ion-permeation properties are conferred by C-terminal region. We further identify a glutamate residue within a conserved region adjacent to the last two putative TM domains of the protein, that when mutated, affects unitary conductance and ion selectivity, and modulates pore block. We propose that this amino acid is either in the pore or closely associates with the pore. Our results describe important structural motifs of this channel family and lay the groundwork for a mechanistic understanding of how Piezos are mechanically gated and conduct ions.


Subject(s)
Drosophila Proteins/chemistry , Ion Channels/chemistry , Amino Acid Sequence , Animals , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , HEK293 Cells , Humans , Ion Channels/genetics , Ion Channels/metabolism , Mice , Molecular Sequence Data
5.
Pflugers Arch ; 467(1): 95-9, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25037583

ABSTRACT

Mechanotransduction is the conversion of mechanical stimuli into biological signals. It is involved in the modulation of diverse cellular functions such as migration, proliferation, differentiation, and apoptosis as well as in the detection of sensory stimuli such as air vibration and mechanical contact. Therefore, mechanotransduction is crucial for organ development and homeostasis and plays a direct role in hearing, touch, proprioception, and pain. Multiple molecular players involved in mechanotransduction have been identified in the past, among them ion channels directly activated by cell membrane deformation. Most of these channels have well-established roles in lower organisms but are not conserved in mammals or fail to encode mechanically activated channels in mammals due to non-conservation of mechanotransduction property. A family of mechanically activated channels that counts only two members in human, piezo1 and 2, has emerged recently. Given the lack of valid mechanically activated channel candidates in mammals in the past decades, particular attention is given to piezo channels and their potential roles in various biological functions. This review summarizes our current knowledge on these ion channels.


Subject(s)
Ion Channels/chemistry , Ion Channels/metabolism , Mechanotransduction, Cellular/physiology , Sensation/physiology , Animals , Humans , Ion Channel Gating/physiology , Models, Biological , Stress, Mechanical , Structure-Activity Relationship
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