TLR2 and TLR4 Modulate Mouse Ileal Motility by the Interaction with Muscarinic and Nicotinic Receptors; 35681486

Irritable bowel syndrome (IBS) is a chronic functional bowel disorder characterized by intestinal dysmotility. Changes in intestinal microbiota (dysbiosis) can lead to alterations in neuro-muscular functions in the gut. Toll-like receptors (TLRs) 2 and 4 recognize intestinal bacteria and are involved in the motor response induced by gastrointestinal (GI) neurotransmitters. Acetylcholine (ACh) is a well-known neurotransmitter involved in the regulation of GI motility. This study aimed to evaluate the role of TLR2 and TLR4 in the intestinal motor-response induced by ACh in the mouse ileum, as well as the expression and function of the muscarinic and nicotinic ACh receptors. Muscle contractility studies showed that the contractions induced by ACh were significantly lower in TLR2-/- and TLR4-/- with respect to WT mice. In WT mice, the contractions induced by ACh were reduced in the presence of AF-DX AF-DX 116 (a muscarinic ACh receptor (mAChR) M2 antagonist), 4-DAMP (a mAChR M3 antagonist), mecamylamine (a nicotinic AChR receptor (nAChR) a3ß4 antagonist) and a-bungarotoxin (a nAChR a7 antagonist). In TLR2-/- mice, the contractions induced by ACh were increased by AF-DX 116 and mecamylamine. In TLR4-/- mice, the contractions induced by ACh were reduced by a-bungarotoxin and 4-DAMP. The mRNA and protein expressions of M3 and a3 receptors were diminished in the ileum from TLR2-/- and TLR4-/- with respect to WT mice. However, the levels of mRNA and protein of ß4 were diminished only in TLR4-/- but not in TLR2-/- mice. In conclusion, our results show that TLR2 and TLR4 modulates the motor responses to ACh in the mouse ileum. TLR2 acts on muscarinic M2 and M3 and nicotinic a3ß4 ACh receptors, while TLR4 acts on muscarinic M3 and nicotinic a3ß4 and a7 ACh receptors

Toll-like receptor 2 modulates the inhibitory motor response induced by hydrogen sulphide in mouse colon

Introduction: The recognition of intestinal microbiota is in part carried out by toll-like receptors (TLR), which are responsible for initiating the innate immune response. Alterations in the intestinal microbiota and its recognition may contribute to the development of intestinal inflammatory pathologies. Otherwise, hydrogen sulphide (H2S) is an endogenous gaseous signalling molecule and it potentially plays a relevant role in the intestinal motility. In mammals, two pyridoxalphosphate-dependent enzymes are responsible for H2S synthesis: cystathionine b-synthase (CBS) and cystathionine -lyase (CSE)..

NOD2 Modulates Serotonin Transporter and Interacts with TLR2 and TLR4 in Intestinal Epithelial Cells

Background/Aims: Serotonin (5-HT) is a chief modulator of intestinal activity. The effects of 5-HT depend on its extracellular availability, which is mainly controlled by serotonin transporter (SERT), expressed in enterocytes. On the other hand, innate immunity, mediated by Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs), is known to control intestinal microbiota and maintain intestinal homeostasis. The dysregulation of the intestinal serotonergic system and innate immunity has been observed in in ammatory bowel diseases (IBD), the incidence of which has severely increased all over the world. The aim of the present study, therefore, was to analyze the effect of NOD2 on intestinal SERT activity and expression, as well as to study the crosstalk of NOD2 with TLR2 and TLR4. Methods: Intestinal epithelial cell line Caco-2/TC7 was used to analyze SERT activity and SERT, NOD2, TLR2 and TLR4 molecular expression by real-time PCR and western blotting. Moreover, intestinal tract (ileum and colon) from mice de cient in TLR2, TLR4 or TLR2/4 receptors was used to test the interdependence of NOD2 with these TLR receptors. Results: NOD2 activation inhibits SERT activity in Caco-2/TC7 cells, mainly due to the decrement of SERT molecular expression, with RIP2/RICK being the intracellular pathway involved in this effect. This inhibitory effect on SERT would yield an increment of extracellular 5-HT availability. In this sense, 5-HT strongly inhibits NOD2 expression. In addition, NOD2 showed greater interdependence with TLR2 than with TLR4. Indeed, NOD2 expression signi cantly increased in both cells treated with TLR2 agonists and the intestinal tract of Tlr2-/- mice. Conclusions: It may be inferred from our data that NOD2 could play a role in intestinal pathophysiology not only through its inherent innate immune role but also due to its interaction with other receptors as TLR2 and the modulation of the intestinal serotonergic system decreasing SERT activity and expression

Toll-like receptor 9 modifies intestinal serotonergic system.

Introduction: Toll-like receptor 9 (TLR9) is expressed in intestinal epithelial cells, which recognize microbiota developing different responses 1. Several studies have shown that TLR9 seems to be involved in Inflammatory Bowel Diseases (IBD) due to an inappropriate defensive response against microorganisms 2. Moreover, intestinal serotonergic system is also altered in IBD, where extracellular serotonin (5–HT) levels are increased 3. 5-HT bioavailability is mainly regulated by the serotonin transporter (SERT), expressed in enterocytes 4. Aims & Methods: The aim of the present study was to analyse whether TLR9 activation affects SERT expression and activity, and expression of other elements from the serotonergic system (TPH1, TPH2 and 5-HT receptors). Human enterocyte-like Caco-2 cells, and ileum and colon from TLR9-/- mice and Dextran Sulphate Sodium (DSS) mouse colitis model were used as experimental models. mRNA expression was determined by RT-qPCR, and protein expression by western blot..

Video-based tasks for emotional processing rehabilitation in schizophrenia

Schizophrenia is a mental disorder characterized by a breakdown of cognitive processes and by a deficit of typi-cal emotional responses. Effectiveness of computerized task has been demonstrated in the field of cognitive rehabilitation. However, current rehabilitation programs based on virtual environments normally focus on higher cognitive functions, not covering social cognition training. This paper presents a set of video-based tasks specifically designed for the rehabilita-tion of emotional processing deficits in patients in early stages of schizophrenia or schizoaffective disorders. These tasks are part of the Mental Health program of Guttmann NeuroPer-sonalTrainer® cognitive tele-rehabilitation platform, and entail innovation both from a clinical and technological per-spective in relation with former traditional therapeutic con-tents

Oral subchronic exposure to the mycotoxin ochratoxin A induces key pathological features of Parkinson's disease in mice six months after the end of the treatment

Some epidemiological studies with different levels of evidence have pointed to a higher risk of Parkinson's disease (PD) after exposure to environmental toxicants. A practically unexplored potential etiological factor is a group of naturally-occurring fungal secondary metabolites called mycotoxins. The mycotoxin ochratoxin A (OTA) has been reported to be neurotoxic in mice. To further identify if OTA exposure could have a role in PD pathology, Balb/c mice were orally treated with OTA (0.21, 0.5 mg/kg bw) four weeks and left for six months under normal diet. Effects of OTA on the onset, progression of alpha-synuclein pathology and development of motor deficits were evaluated. Immunohistochemical and biochemical analyses showed that oral subchronic OTA treatment induced loss of striatal dopaminergic innervation and dopaminergic cell dysfunction responsible for motor impairments. Phosphorylated alpha-synuclein levels were increased in gut and brain. LAMP-2A protein was decreased in tissues showing alpha-synuclein pathology. Cell cultures exposed to OTA exhibited decreased LAMP-2A protein, impairment of chaperone-mediated autophagy and decreased alpha-synuclein turnover which was linked to miRNAs deregulation, all reminiscent of PD. These results support the hypothesis that oral exposure to low OTA doses in mice can lead to biochemical and pathological changes reported in PD

Developing an Integrated Ocean Observing System for New Zealand

New Zealand (NZ) is an island nation with stewardship of an ocean twenty times larger than its land area. While the challenges facing NZ’s ocean are similar to other maritime countries, no coherent national plan exists that meets the needs of scientists, stakeholders or kaitiakitanga (guardianship) of NZ’s ocean in a changing climate. The NZ marine science community used the OceanObs’19 white paper to establish a framework and implementation plan for a collaborative NZ ocean observing system (NZ-OOS). Co-production of ocean knowledge with Māori will be embedded in this national strategy for growing a sustainable, blue economy for NZ. The strengths of an observing system for a relatively small nation come from direct connections between the science impetus through to users and stakeholders of an NZ-OOS. The community will leverage off existing ocean observations to optimize effort and resources in a system that has historically made limited investment in ocean observing. The goal of the community paper will be achieved by bringing together oceanographers, data scientists and marine stakeholders to develop an NZ-OOS that provides best knowledge and tools to the sectors of society that use or are influenced by the ocean

Geometry and reactivity in crystalline solids formed by transition metal citrate cubanes

Trabajo presentado al American Crystallographic Association Annual Meeting celebrado en Boston (US) del 28 de julio al 1 de agosto de 2012.Transition metals (M) and quadruply deprotonated citrate (citr4-) form complexes with [M4(citr)4](8-) structural building blocks that have at their cores an M4O4 unit with cubane topology. At the periphery of the [M4(citr)4](8-) unit is an icosahedron formed by twelve oxygen atoms with partial negative charges, to which metal atoms can bind in a number of ways to give products with discrete molecular structures or with 1-, 2-, and 3-D polymers in the crystalline state. In addition to geometrically regular and irregular shapes, some of these products also display reactivity in the solid state, with reversible chemical processes having been observed to change the dimension of the polymer or to produce ion transfer with structual modulation. The geometries of the products reported to date are analyzed systematically in this presentation, and the geometrical relationships between reactants and products in a topotactic solid-state reaction are explored in detail. Unusual solvent uptake and loss in some of these solids is described, with reference to the structural features which enable this behavior.Funding is provided by the Ministry of Science and Innovation (Spain), Grant MAT2011-27233- C02-01 and CONSOLIDER-INGENIO in Molecular Nanoscience, ref. CSD 2007-00010. Additional funding is provided by the Regional Government of Aragón.Peer reviewe

Comments on proton cascade in a molecular solid: H/D exchange on mobile and immobile water

7th Meeting of the Spanish Neutron Scattering Association (SETN).Following a previous report of proton transport in a channel-free molecular solid possessing a complex set of water wires, the mechanisms implied by the available neutron diffraction measurements are further developed. Three specific proton transfer pathways along an experimentally observed water wire are proposed. The first is proton transfer involving two aqua ligands coordinated to the same Mn(II) unit and one free water acting as a shuttle. The second mechanism consists of proton transfer between coordinated aqua ligands of distinct molecules, with no shuttle. The third mechanism involves a component of vehicle transport, involving a water molecule that changes position during the process. Geometric parameters of the proposed mechanisms are given.Funding was provided by the Ministerio de Ciencia e Innovación (Spain) under Grants MAT2011-27233-C02-01 and MAT2011-27233-C02-02 with cofinancing from the European Union Regional Development Fund (FEDER), and under the program CONSOLIDER-INGENIO in Molecular Nanoscience (reference CSD 2007-00010). EFV thanks the Ministry of Education (Spain) for a pre-doctoral scholarship under the program ‘Becas y Contratos FPU’ (reference AP2009-4211). Funding was also provided by the Diputación General de Aragón (Spain). The authors acknowledge the services of the Servicio General de Apoyo a la Investigación – SAI, University of Zaragoza.Peer Reviewe

A square two-dimensional polymer of cobalt citrate cubanes

5 páginas, 4 figuras, 2 tablas.The structure of the title complex, poly[dicaesium(I) hexaaquacobalt(II) [octaaquatetra--citrato-hexacobalt(II)] dodecahydrate], {Cs2[Co(H2O)6][Co6(C6H4O7)4(H2O)8]·12H2O}n, at 100 (1) K is formed by layers of a square two-dimensional polymer composed of CoII citrate cubanes bridged by magnetically active six-coordinate CoII cations. The polymer has plane symmetry p4mm in the c-axis projection. The cubanes reside on sites of crystallographic symmetry , while the bridging CoII centres lie on twofold axes. The basic polymeric unit has a charge of 4-, balanced by two Cs+ and a [Co(H2O)6]2+ (symmetry ) cation, which lie in channels between the polymeric layers. Unligated water molecules, of which there are 12 per cubane, enter into an extended intralayer and layer-bridging hydrogen-bond pattern, which can be described in detail even though not all of the H atoms of the water molecules were located.This work was supported by the Ministry of Science and Innovation (Spain) under grant Nos. MAT2007-61621, MAT2008-04350 and CONSOLIDER-INGENIO in Molecular Nanoscience (reference CSD 2007-00010), and by the Diputación General de Aragón (Spain). EFV thanks the Ministry of Education (Spain) for a pre-doctoral scholarship under the programme ‘Becas y Contratos FPU’ (reference AP2009-4211)Peer reviewe