Interaction between nanomaterials and the innate immune system across evolution

Interaction of engineered nanomaterials (ENMs) with the immune system mainly occurs with cells and molecules of innate immunity, which are present in interface tissues of living organisms. Immuno-nanotoxicological studies aim at understanding if and when such interaction is inconsequential or may cause irreparable damage. Since innate immunity is the first line of immune reactivity towards exogenous agents and is highly conserved throughout evolution, this review focuses on the major effector cells of innate immunity, the phagocytes, and their major sensing receptors, Toll-like receptors (TLRs), for assessing the modes of successful versus pathological interaction between ENMs and host defences. By comparing the phagocyte- and TLR-dependent responses to ENMs in plants, molluscs, annelids, crustaceans, echinoderms and mammals, we aim to highlight common recognition and elimination mechanisms and the general sufficiency of innate immunity for maintaining tissue integrity and homeostasis.     

Human cleft lip and palate fibroblasts and normal nicotine‐treated fibroblasts show altered in vitro expressions of genes related to molecular signaling pathways and extracellular matrix metabolism

Nonsyndromic cleft lip with or without cleft palate (CLP) is a frequent craniofacial malformation caused by both genetic and environmental factors. Maternal smoking during pregnancy is a known risk factor, due to the teratogenic role of nicotine. To assess and compare the impact of CLP and nicotine, we studied the quantitative expression of genes involved in signaling pathways and extracellular matrix (ECM) metabolism in human normal nicotine‐treated (NicN) and CLP fibroblasts compared to normal control (CTRL) cells. Palatal fibroblast cultures from seven CLP children and seven age‐matched CTRL subjects were established and subconfluent cells incubated for 24 h without (CTRL and CLP fibroblasts) or with (NicN fibroblasts) 0.6 mM nicotine. Gene expressions were analyzed by real‐time quantitative PCR. For the first time, a regulated cholinergic signaling in our human fibroblasts in vitro was demonstrated. Members of TGF‐beta, retinoic acid (RA), and GABA‐ergic signaling systems were also differently regulated. Among the ECM genes, fibronectin, syndecan, integrin α2, and MMP13 genes were concordantly modulated, while integrin β5, and decorin genes were discordantly modulated. Interestingly, nicotine treatment regulated gene expressions of CD44 and CLPTM1, two candidate genes for CLP. Our findings show a positive association between nicotine treatment and CLP phenotype. Results suggest that nicotine deranges normal palate development, which might contribute to the development of a CLP malformative phenotype, through the impairment of some important signaling systems and ECM composition. J. Cell. Physiol. 222: 748–756, 2010. © 2009 Wiley‐Liss, Inc.     

Optically activated and interrogated plasmonic hydrogels for applications in wound healing

We disclose the use of hybrid materials featuring Au/Ag core/shell nanorods in porous chitosan/polyvinyl alcohol scaffolds for applications in tissue engineering and wound healing. The combination of Au and Ag in a single construct provides synergistic opportunities for optical activation of functions as near infrared laser tissue bonding, and remote interrogation to return parameters of prognostic relevance in wound healing monitoring. In particular, the bimetallic component ensures optical tunability, enhanced shelf life and photothermal stability, serves as a reservoir of germicidal silver cations, and changes in near‐infrared and visible color according to the environmental level of oxidative stress. At the same time, the polymeric blend is ideal to bind connective tissue upon photothermal activation, and to support fabrication processes that provide high porosity, such as electrospinning, thus putting all the premises for cellular repopulation and antimicrobial protection.     

Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids

The prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are “addicted” to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APC^Min/+ mice intestinal organoids revealed that p38α acts as a β-catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38α kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38α may be targeted in CSCs to devise new personalized CRC treatment strategies.Subject terms: Cancer stem cells, Colorectal cancer, Post-translational modifications     

Stenting-induced Vasa Vasorum compression and subsequent flow resistance: a finite element study

Biomechanics and Modeling in Mechanobiology - Vascular stenting is a common intervention for the treatment for atherosclerotic plaques. However, stenting still has a significant rate of restenosis...     

Correction of the defective extracellular matrix of Ehlers-Danlos syndrome skin fibroblasts by dexamethasone.

Skin fibroblasts derived from Ehlers-Danlos syndrome (EDS) patients lack an organized extracellular matrix (ECM) of fibronectin (FN) and often show an accumulation of cytoplasmic FN. The treatment of EDS cells of different types (I to VIII) with 10-⁷ M dexamethasone (dex), as well as cocultivation with control fibroblasts, induced in most cases the assembly of a FN-like ECM. The study of FN mRNA expression by dot-blot hybridization and of FN released into the culture media of EDS cells showed that the correction of the defective FN-ECM of EDS cells by dex treatment is associated in most cases with an increase of FN mRNA synthesis and of secreted FN.     

Analysis of Oxidative Stress in Zebrafish Embryos

High levels of reactive oxygen species (ROS) may cause a change of cellular redox state towards oxidative stress condition. This situation causes oxidation of molecules (lipid, DNA, protein) and leads to cell death. Oxidative stress also impacts the progression of several pathological conditions such as diabetes, retinopathies, neurodegeneration, and cancer. Thus, it is important to define tools to investigate oxidative stress conditions not only at the level of single cells but also in the context of whole organisms. Here, we consider the zebrafish embryo as a useful in vivo system to perform such studies and present a protocol to measure in vivo oxidative stress. Taking advantage of fluorescent ROS probes and zebrafish transgenic fluorescent lines, we develop two different methods to measure oxidative stress in vivo: i) a “whole embryo ROS-detection method” for qualitative measurement of oxidative stress and ii) a “single-cell ROS detection method” for quantitative measurements of oxidative stress. Herein, we demonstrate the efficacy of these procedures by increasing oxidative stress in tissues by oxidant agents and physiological or genetic methods. This protocol is amenable for forward genetic screens and it will help address cause-effect relationships of ROS in animal models of oxidative stress-related pathologies such as neurological disorders and cancer.     

Asymmetric Synthesis of Optically Active 1,3-Oxathiolane Nucleoside Analogues

Abstract

A ready asymmetric synthesis of 3′-oxa-4′-thionucleosides has been accomplished in three main steps from benzoyloxyethanal. The synthesis is characterized by high overall yield and appreciable enantiomeric excesses. It represents a general synthetic scheme to prepare a wide range of heterosubstituted sulfur-containing nucleoside analogues.     

Ser/Thr kinases and polyamines in the regulation of non-canonical functions of elongation factor 1A

The link between eukaryotic translation elongation factor 1A (eEF1A) and signal transduction pathways through the regulatory mechanism of phosphorylation has never been considered. In this review, we focus on the different kinases that recognize the Ser and Thr residues of the eEF1A1 and eEF1A2 isoforms and regulate their involvement in different cellular processes like cell survival and apoptosis. In this context, polyamines seem to play a role in the regulation of the translation elongation process by modulating the Ser/Thr kinases involved in the phosphorylation of translation elongation factors.     

Interspecific variation of ontogeny and skull shape among porpoises (Phocoenidae)

All extant members of Phocoenidae (porpoises) have been characterized as pedomorphic based on skeletal characters. To investigate the ontogenetic background for pedomorphosis and assess interspecific differences in ontogeny among phocoenids, samples of the six extant species were compared in terms of development of both epiphyseal and cranial suture fusion. Across all species, full maturity of the vertebral column was rare. Vertebral epiphyseal development did not progress so far in most Phocoena phocoena as in Phocoenoides dalli and Phocoena dioptrica. P. phocoena, Phocoena spinipinnis, Ph. dalli, and P. dioptrica, for which large series were available, were further compared in terms of ontogeny of cranial shape by three‐dimensional geometric morphometrics. Ph. dalli and P. dioptrica generally showed further development of cranial sutures than the other species. Postnatal skull shape development was similar for all species studied; the majority of interspecific shape differences are present at parturition. Smaller species had a higher rate of shape development relative to growth in size than Ph. dalli and P. dioptrica, but they still showed less allometric development due to less postnatal growth. Interspecific shape differences indicate phylogenetic relationships similar to that proposed based on morphology or convergent evolution of the two pelagic species, Ph. dalli and P. dioptrica, under the scenarios suggested by recent molecular studies. A shape trend coinciding with habitat preference was detected; in species with pelagic preference the position and orientation of the foramen magnum aligned the skull with the vertebral column; the rostrum showed less ventral inclination, and the facial region was larger and more concave in lateral aspect. J. Morphol., 2011. © 2010 Wiley‐Liss, Inc.