Engineered nanomaterials induce alterations in biological barriers: focus on paracellular permeability

Engineered nanoparticles (ENPs) are widely used in medical diagnosis and treatment, as food additives and as energy materials. ENPs may exert adverse or beneficial effects on the human body, which may be linked to interactions with biological barriers. In this review, the authors summarize the influences of four typical metal/metal oxide nanomaterials (Ag, TiO2, Au, ZnO nanoparticles) on the paracellular permeability of biological barriers. Disruptions on tight junctions, adhesion junctions, gap junctions and desmosomes via complex signaling pathways, such as the MAPK, PKC and ROCK signaling pathways, affect paracellular permeability. Reactive oxygen species and cytokines underlie the mechanism of ENP-triggered alterations in paracellular permeability. This review provides the information necessary for the cautious application of nanoparticles in medicine and life sciences in the future.

New Mechanism For Mesenchymal Stem Cell Microvesicle To Restore Lung Permeability: Intracellular S1P Signaling Pathway Independent of S1P Receptor-1

Background: Microvesicles (MV) derived from human bone marrow mesenchymal stem cell (MSC) were demonstrated to restore lung protein permeability and attenuate acute lung injury (ALI). In our previous study, we found that MSC MV increased sphingosine 1 phosphate (S1P) kinase1 mRNA levels in injured human lung microvascular endothelial cells (HLMVEC) significantly. However, the role of S1P signaling in MSC MV to restore lung protein permeability is unknown.Methods: In this study, we hypothesized that MSC MV might restore lung permeability in part through increasing intracellular S1P signaling pathway in injured HLMVEC independent of S1P receptors. We used the transwell co-culture system to study the effect of MSC MV on protein permeability of Lipopolysaccharide (LPS) damaged HLMVEC. Results: Our results showed that LPS significantly increased the permeability of HLMVEC to FITC-dextran (70 kDa) within 24 hours. MSC MV restores this permeability, and to a large extent prevents the cytoskeleton protein F-actin from recombining into "actin stress fibers", and restores the positions of tight junctions and adhesion junctions in the damaged HLMVEC. This therapeutic effect of MSC MV was related to the increase in the S1P level in injured HLMVEC and was not eliminated when adding the antagonist of S1P receptor, suggesting that MSC MV to restore lung permeability was independent of S1P receptors on HLMVEC. Laser confocal further observed that Ca2+ mobilization and Rac1 activiation in LPS injured HLMVEC were increased in parallel with the increase in intracellular S1P level after MSC MV treatment. Conclusions: In short, MSC MV partially restored protein permeability across HLMVEC through the intracellular S1P signaling pathway independent of S1P receptor-1.

Expression Analysis of Circular RNAs in Young and Sexually Mature Boar Testes

Testicular development is critical for male animals’ reproduction and is tightly regulated by epigenetic factors. Circular RNAs (circRNAs) were recently identified in the testes of humans and bulls. However, the expression profile of circRNAs and their potential biological functions in boar testicular development remain unclear. We identified 34,521 and 31,803 circRNAs in piglet (30 d) and adult (210 d) boar testes by high-throughput sequencing, respectively. Bioinformatics analysis revealed that these circRNAs are widely distributed on autosomes and sex chromosomes. Some of the host genes can generate multiple circRNAs. A total of 2326 differentially expressed circRNAs (DECs) derived from 1526 host genes was found in testicular development, of which 1003 circRNAs were up-regulated in adult boar testes and 1323 circRNAs were down-regulated. Furthermore, gene ontology analysis of host genes of DECs revealed that these circRNAs are mainly involved in regulating spermatogenesis, cilia motility, and hormone biosynthesis. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that the DECs are markedly enriched to stem cell pluripotency regulation, tight junctions, adhesion junctions, and cAMP signaling pathway. These results indicate that circRNAs are abundantly expressed in boar testes and exhibit dynamic changes during testicular development.

The TRIOBP Isoforms and Their Distinct Roles in Actin Stabilization, Deafness, Mental Illness, and Cancer

The TRIOBP (TRIO and F-actin Binding Protein) gene encodes multiple proteins, which together play crucial roles in modulating the assembly of the actin cytoskeleton. Splicing of the TRIOBP gene is complex, with the two most studied TRIOBP protein isoforms sharing no overlapping amino acid sequence with each other. TRIOBP-1 (also known as TARA or TAP68) is a mainly structured protein that is ubiquitously expressed and binds to F-actin, preventing its depolymerization. It has been shown to be important for many processes including in the cell cycle, adhesion junctions, and neuronal differentiation. TRIOBP-1 has been implicated in schizophrenia through the formation of protein aggregates in the brain. In contrast, TRIOBP-4 is an entirely disordered protein with a highly specialized expression pattern. It is known to be crucial for the bundling of actin in the stereocilia of the inner ear, with mutations in it causing severe or profound hearing loss. Both of these isoforms are implicated in cancer. Additional longer isoforms of TRIOBP exist, which overlap with both TRIOBP-1 and 4. These appear to participate in the functions of both shorter isoforms, while also possessing unique functions in the inner ear. In this review, the structures and functions of all of these isoforms are discussed, with a view to understanding how they operate, both alone and in combination, to modulate actin and their consequences for human illness.

Phospholipase D2 restores endothelial barrier function by promoting PTPN14-mediated VE-cadherin dephosphorylation

Increased permeability of vascular lung tissues is a hallmark of acute lung injury and is often caused by edemagenic insults resulting in inflammation. Vascular endothelial (VE)-cadherin undergoes internalization in response to inflammatory stimuli and is recycled at cell adhesion junctions during endothelial barrier re-establishment. Here, we hypothesized that phospholipase D (PLD)-generated phosphatidic acid (PA) signaling regulates VE-cadherin recycling and promotes endothelial barrier recovery by dephosphorylating VE-cadherin. Genetic deletion of PLD2 impaired recovery from protease-activated receptor-1–activating peptide (PAR-1–AP)-induced lung vascular permeability and potentiated inflammation in vivo. In human lung microvascular endothelial cells (HLMVECs), inhibition or deletion of PLD2, but not of PLD1, delayed endothelial barrier recovery after thrombin stimulation. Thrombin stimulation of HLMVECs increased co-localization of PLD2-generated PA and VE-cadherin at cell-cell adhesion junctions. Inhibition of PLD2 activity resulted in prolonged phosphorylation of Tyr-658 in VE-cadherin during the recovery phase 3 h post-thrombin challenge. Immunoprecipitation experiments revealed that after HLMVECs are thrombin stimulated, PLD2, VE-cadherin, and protein-tyrosine phosphatase nonreceptor type 14 (PTPN14), a PLD2-dependent protein-tyrosine phosphatase, strongly associate with each other. PTPN14 depletion delayed VE-cadherin dephosphorylation, reannealing of adherens junctions, and barrier function recovery. PLD2 inhibition attenuated PTPN14 activity and reversed PTPN14-dependent VE-cadherin dephosphorylation after thrombin stimulation. Our findings indicate that PLD2 promotes PTPN14-mediated dephosphorylation of VE-cadherin and that redistribution of VE-cadherin at adherens junctions is essential for recovery of endothelial barrier function after an edemagenic insult.

A Mechanical Model of Early Somite Segmentation

The clock-and-wavefront model (CW) hypothesizes that the formation of somites in vertebrate embryos results from the interplay of molecular oscillations with a wave traveling along the body axis. This model however does not explain how molecular information is interpreted by cells to modulate their rearrangement into somites. Here we performed Scanning Electron Microscopy (SEM) on the pre-somitic mesoderm (PSM) of chicken embryos at stages 11-12 to describe in detail the cell shape changes occurring along the axis of the PSM. This reveals a wave of epithelialization of the dorsal PSM that precedes somite segmentation. Signs of spatially periodic apical constriction appear in this layer starting at least 3-4 somite lengths caudal to the most recently formed somite. The sizes of these clusters correspond to the typical diameter of chicken somites. We propose that a mechanical instability process leads to the separation of cells into these structures and positions the future inter-somite boundaries. We present a model in which a wave of apical constriction leads to increasing tension and periodic failure of adhesion junctions within the dorsal epithelial layer of the PSM, thus positioning somite boundaries. This model can produce spatially periodic segments whose size depends on the speed of the contraction wave (W) and the rate of increase of apical contractility (Λ). The Λ/W ratio determines whether this mechanism produces spatially and temporally regular or irregular segments, and whether segment sizes increase with the wave speed (scaling) as in the CW model. We discuss the limitations of a purely mechanical model of somite segmentation and the role of biomechanics along with CW during somitogenesis.

Wheat gluten intake increases the severity of experimental colitis and bacterial translocation by weakening of the proteins of the junctional complex

Gluten is only partially digested by intestinal enzymes and can generate peptides that can alter intestinal permeability, facilitating bacterial translocation, thus affecting the immune system. Few studies addressed the role of diet with gluten in the development of colitis. Therefore, we investigate the effects of wheat gluten-containing diet on the evolution of sodium dextran sulphate (DSS)-induced colitis. Mice were fed a standard diet without (colitis group) or with 4·5 % wheat gluten (colitis + gluten) for 15 d and received DSS solution (1·5 %, w/v) instead of water during the last 7 d. Compared with the colitis group, colitis + gluten mice presented a worse clinical score, a larger extension of colonic injury area, and increased mucosal inflammation. Both intestinal permeability and bacterial translocation were increased, propitiating bacteria migration for peripheral organs. The mechanism by which diet with gluten exacerbates colitis appears to be related to changes in protein production and organisation in adhesion junctions and desmosomes. The protein α-E-catenin was especially reduced in mice fed gluten, which compromised the localisation of E-cadherin and β-catenin proteins, weakening the structure of desmosomes. The epithelial damage caused by gluten included shortening of microvilli, a high number of digestive vacuoles, and changes in the endosome/lysosome system. In conclusion, our results show that wheat gluten-containing diet exacerbates the mucosal damage caused by colitis, reducing intestinal barrier function and increasing bacterial translocation. These effects are related to the induction of weakness and disorganisation of adhesion junctions and desmosomes as well as shortening of microvilli and modification of the endocytic vesicle route.

Bullous disorders

This chapter focuses on immunobullous diseases. The immunobullous disorders are a group of diseases in which pathogenic autoantibodies bind to target antigens either in desmosomes (intra-epidermal intracellular adhesion junctions) or in part of the basement membrane zone, resulting in loss of adhesion, and blister formation. This chapter will focus on pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, linear IgA disease, chronic bullous disease of childhood, and dermatitis herpetiformis; it will also mention mucous membrane pemphigoid, pemphigoid gestationis, and epidermolysis bullosa acquisita.

The endoplasmic reticulum, calcium signaling and junction turnover in Sertoli cells

The endoplasmic reticulum (ER) forms a continuous network throughout morphologically differentiated Sertoli cells. It is an integral component of intercellular adhesion junctions in this cell type, as well as forming membrane contact sites with the plasma membrane and intracellular organelles. One of the major functions of the ER in cells generally is maintaining calcium homeostasis and generating calcium signals. In this review, we discuss what is currently known about the overall pattern of distribution of the ER in Sertoli cells and the location of calcium regulatory machinery in the various subdomains of the organelle. Current data is consistent with the hypothesis that calcium signaling by the ER of Sertoli cells may play a significant role in events related to junction remodeling that occur in the seminiferous epithelium during spermatogenesis.