Comparative Analysis of the Physicochemical and Biological Characteristics of Freeze-Dried PEGylated Cationic Solid Lipid Nanoparticles.

Cationic solid-lipid nanoparticles (cSLNs) have become a promising tool for gene and RNA therapies. PEGylation (PEG) is crucial in enhancing particle stability and protection. We evaluated the impact of PEG on the physicochemical and biological characteristics of cholesteryl-oleate cSLNs (CO-cSLNs).

Neuropeptide Cortistatin Regulates Dermal and Pulmonary Fibrosis in an Experimental Model of Systemic Sclerosis.

Introduction: Scleroderma, or systemic sclerosis, is a complex connective tissue disorder characterized by autoimmunity, vasculopathy, and progressive fibrosis of the skin and internal organs. Because its aetiology is unknown, the identification of genes/factors involved in disease severity, differential clinical forms, and associated complications is critical for understanding its pathogenesis and designing novel treatments. Neuroendocrine mediators in the skin emerge as potential candidates.

Protective role of cortistatin in pulmonary inflammation and fibrosis.

Background And Purpose: Acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and pulmonary fibrosis remain major causes of morbidity, mortality and a healthcare burden in critically ill patient. There is an urgent need to identify factors causing susceptibility and for the design of new therapeutic agents. Here, we evaluate the effectiveness of the immunomodulatory neuropeptide cortistatin to regulate pulmonary inflammation and fibrosis in vivo.

An update on redox signals in plant responses to biotic and abiotic stress crosstalk: insights from cadmium and fungal pathogen interactions.

Complex signalling pathways are involved in plant protection against single and combined stresses. Plants are able to coordinate genome-wide transcriptional reprogramming and display a unique programme of transcriptional responses to a combination of stresses that differs from the response to single stresses. However, a significant overlap between pathways and some defence genes in the form of shared and general stress-responsive genes appears to be commonly involved in responses to multiple biotic and abiotic stresses.

Human prefoldin modulates co-transcriptional pre-mRNA splicing.

Prefoldin is a heterohexameric complex conserved from archaea to humans that plays a cochaperone role during the co-translational folding of actin and tubulin monomers. Additional functions of prefoldin have been described, including a positive contribution to transcription elongation and chromatin dynamics in yeast. Here we show that prefoldin perturbations provoked transcriptional alterations across the human genome.

Innovative Therapeutic and Delivery Approaches Using Nanotechnology to Correct Splicing Defects Underlying Disease.

Alternative splicing of pre-mRNA contributes strongly to the diversity of cell- and tissue-specific protein expression patterns. Global transcriptome analyses have suggested that >90% of human multiexon genes are alternatively spliced. Alterations in the splicing process cause missplicing events that lead to genetic diseases and pathologies, including various neurological disorders, cancers, and muscular dystrophies.

Prp40 localizes to the histone locus body and regulates gene transcription and development.

In eukaryotes, a large amount of histones need to be synthesized during the S phase of the cell cycle to package newly synthesized DNA into chromatin. The transcription and 3' end processing of histone pre-mRNAs are controlled by the histone locus body (HLB), which is assembled on the shared promoter for and Here, we identified the Prp40 pre-mRNA processing factor (dPrp40, annotated as CG3542) as a novel HLB component. We showed that dPrp40 is essential for development, with functionally conserved activity in vertebrates and invertebrates.

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics.

A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression.

Formulation of Direct Compression Zidovudine Tablets to Correlate the SeDeM Diagram Expert System and the Rotary Press Simulator Styl'ONE Results.

The SeDeM diagram expert system has been applied to study Zidovudine and some excipients. From the obtained diagrams, a pharmaceutical formula has been designed. SeDeM diagram ascertains the critical parameters that are suitable for a direct compression.

Role for the splicing factor TCERG1 in Cajal body integrity and snRNP assembly.

Cajal bodies are nuclear organelles involved in the nuclear phase of small nuclear ribonucleoprotein (snRNP) biogenesis. In this study, we identified the splicing factor TCERG1 as a coilin-associated factor that is essential for Cajal body integrity. Knockdown of TCERG1 disrupts the localization of the components of Cajal bodies, including coilin and NOLC1, with coilin being dispersed in the nucleoplasm into numerous small foci, without affecting speckles, gems or the histone locus body.

Development and characterization of an improved formulation of cholesteryl oleate-loaded cationic solid-lipid nanoparticles as an efficient non-viral gene delivery system.

Nanoparticle-mediated plasmid delivery is considered a useful tool to introduce foreign DNA into the cells for the purpose of DNA vaccination and/or gene therapy. Cationic solid-lipid nanoparticles (cSLNs) are considered one of the most promising non-viral vectors for nucleic acid delivery. Based on the idea that the optimization of the components is required to improve transfection efficiency, the present study aimed to formulate and characterize cholesteryl oleate-containing solid-lipid nanoparticles (CO-SLNs) incorporating protamine (P) to condense DNA to produce P:DNA:CO-SLN complexes as non-viral vectors for gene delivery with reduced cytotoxicity and high cellular uptake efficiency.

Improved synthesis and characterization of cholesteryl oleate-loaded cationic solid lipid nanoparticles with high transfection efficiency for gene therapy applications.

The development of new nanoparticle formulations that are capable of high transfection efficiency without toxicity is essential to provide new tools for gene therapy. However, the issues of complex, poorly reproducible manufacturing methods, and low efficiencies during in vivo testing have prevented translation to the clinic. We have previously reported the use of cholesteryl oleate as a novel excipient for solid lipid nanoparticles (SLNs) for the development of highly efficient and nontoxic nucleic acid delivery carriers.

Identification of TCERG1 as a new genetic modulator of TDP-43 production in Drosophila.

TAR DNA-binding protein-43 (TDP-43) is a ubiquitously expressed DNA-/RNA-binding protein that has been linked to numerous aspects of the mRNA life cycle. Similar to many RNA-binding proteins, TDP-43 expression is tightly regulated through an autoregulatory negative feedback loop. Cell function and survival depend on the strict control of TDP-43 protein levels.

Optimization of the Cohesion Index in the SeDeM Diagram Expert System and application of SeDeM Diagram: An improved methodology to determine the Cohesion Index.

In this study, we suggest optimizing the methodology to determine the Cohesion Index (Icd) in order to avoid mistaken characterizations due to powder bulk density. For this purpose, five different excipients, with different bulk densities and of different chemical nature, were compressed at different heights. Their compression and their tablet characterization enable establishing a powder weight for compression in accordance with its bulk density.

Cholesteryl oleate-loaded cationic solid lipid nanoparticles as carriers for efficient gene-silencing therapy.

Background: Cationic solid lipid nanoparticles (SLNs) have been given considerable attention for therapeutic nucleic acid delivery owing to their advantages over viral and other nanoparticle delivery systems. However, poor delivery efficiency and complex formulations hinder the clinical translation of SLNs.

Aim: The aim of this study was to formulate and characterize SLNs incorporating the cholesterol derivative cholesteryl oleate to produce SLN-nucleic acid complexes with reduced cytotoxicity and more efficient cellular uptake.

Targeting proteins to RNA transcription and processing sites within the nucleus.

Studies of the spatial organization of the highly compartmentalized eukaryotic nucleus and dynamics of transcription and RNA processing within it are fundamental for fully understanding how gene expression is regulated in the cell. Although some progress has been made in deciphering the functional consequences of this complex network of interacting molecules in the context of nuclear organization, how proteins and RNA move in the nucleus and how the transcription and RNA processing machineries find their targets are important questions that remain largely unexplored. Here, we review major hallmarks and novel insights regarding the movement of RNA and proteins in the context of nuclear organization as well as the mechanisms by which the proteins involved in RNA processing localize to specific nuclear compartments.

Targeting Splicing in the Treatment of Human Disease.

The tightly regulated process of precursor messenger RNA (pre-mRNA) alternative splicing (AS) is a key mechanism in the regulation of gene expression. Defects in this regulatory process affect cellular functions and are the cause of many human diseases. Recent advances in our understanding of splicing regulation have led to the development of new tools for manipulating splicing for therapeutic purposes.

Transcriptional Elongation Regulator 1 Affects Transcription and Splicing of Genes Associated with Cellular Morphology and Cytoskeleton Dynamics and Is Required for Neurite Outgrowth in Neuroblastoma Cells and Primary Neuronal Cultures.

TCERG1 is a highly conserved human protein implicated in interactions with the transcriptional and splicing machinery that is associated with neurodegenerative disorders. Biochemical, neuropathological, and genetic evidence suggests an important role for TCERG1 in Huntington's disease (HD) pathogenesis. At present, the molecular mechanism underlying TCERG1-mediated neuronal effects is unknown.

Improved formulation of cationic solid lipid nanoparticles displays cellular uptake and biological activity of nucleic acids.

Non-viral delivery using cationic solid lipid nanoparticles (SLNs) represents a useful strategy to introduce large DNA and RNA molecules to target cells. A careful selection of components and their amounts is critical to improve transfection efficiency. In this work, a selected and optimized formulation of SLNs was used to efficiently transfect circular DNA and linear RNA molecules into cells.

Association of HLA-B*41:02 with Henoch-Schönlein Purpura (IgA Vasculitis) in Spanish individuals irrespective of the HLA-DRB1 status.

Introduction: A study was conducted to determine whether the human leukocyte antigen (HLA) B alleles are implicated in the susceptibility to Henoch-Schönlein purpura (HSP) in the largest series of Caucasian HSP patients ever assessed for genetic studies.

Methods: The study population was composed of 349 Spanish patients diagnosed with HSP fulfilling the American College of Rheumatology and the Michel et al. classification criteria, and 335 sex and ethnically matched controls.