Thyroid Hormone, Thyroid Hormone Metabolites and Mast Cells: A Less Explored Issue.

Mast cells are primary players in immune and inflammatory diseases. In the brain, mast cells are located at the brain side of the blood brain barrier (BBB) exerting a crucial role in protecting the brain from xenobiotic invasion. Furthermore, recent advances in neuroscience indicate mast cells may play an important role in glial cell-neuron communication through the release of mediators, including histamine. Interestingly, brain mast cells contain not only 50% of the brain histamine but also hormones, proteases and lipids or amine mediators; and cell degranulation may be triggered by different stimuli activating membrane bound receptors including the four types of histaminergic receptors. Among hormones, mast cells can store thyroid hormone (T3) and express membrane-bound thyroid stimulating hormone receptors (TSHRs), thus suggesting from one side that thyroid function may affect mast cells function, from the other that mast cell degranulation may impact on thyroid function. In this respect, the research on hormones in mast cells is scarce. Recent pharmacological evidence indicates the existence of a non-genomic portion of the thyroid secretion including thyroid hormone metabolites. Among which the 3,5 diiodothyronine (3,5-T2), 3-iodothyroanamine (T1AM) and 3-iodothyroacetic acid (TA1) are the most studied. All these compounds are endogenously occurring and found to be increased in inflammatory-based diseases involving mast cells. T1AM and TA1 induce, as T3, neuroprotective effects and itch but also hyperalgesia in rodents with a mechanism largely unknown but mediated by the release of histamine. Due to the rapid onset of their effectiveness they may trigger histamine release from a cell where it is "ready-to-be released," i.e., mast cells. Following a very thin path which passes through old experimental and clinical evidence, at the light of novel acquisitions on endogenous T3 metabolites, we aim to stimulate the attention on the possibility that mast cell histamine may be the connector of a novel (neuro) endocrine pathway linking the thyroid with mast cells

N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB) prevents 3-iodothyronamine (T1AM)-induced neuroprotection against kainic acid toxicity

Thyroid hormone and thyroid hormone metabolites, including 3-iodothyronamine (T1AM) and 3-iodothyroacetic acid (TA1), activate AKT signaling in hippocampal neurons affording protection from excitotoxic damage. We aim to explore whether the mechanism of T1AM neuroprotection against kainic acid (KA)-induced excitotoxicity included the activation of the trace amine associated receptor isoform 1 (TAAR1), one of T1AM targets. Rat organotypic hippocampal slices were exposed to vehicle (Veh) or to 5 μM kA for 24 h in the absence or presence of 0.1, 1 and 10 μM T1AM or to 0.1, 1 and 10 μM T1AM and 1 μM N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB), the only available TAAR1 antagonist, or to 1 μM T1AM in the absence or in the presence of 10 μM LY294002, an inhibitor of phosphoinositide 3-kinases (PI3Ks). Cell death was evaluated by measuring propidium iodide (PI) levels of fluorescence 24 h after treatment. In parallel, the expression levels of p-AKT and p-PKA were evaluated by Western blot analysis of slice lysates. The activity of mitochondrial monoamine oxidases (MAO) was assayed fluorimetrically. 24 h exposure of slices to T1AM resulted in the activation of AKT and PKA. KA exposure induced cell death in the CA3 region and significantly reduced p-AKT and p-PKA levels. The presence of 1 and 10 μM T1AM significantly protected neurons from death and conserved both kinase levels with the essential role of AKT in neuroprotection. Furthermore, EPPTB prevented T1AM-induced neuroprotection, activation of PKA and AKT. Of note, in the presence of EPPTB T1AM degradation by MAO was reduced. Our results indicate that the neuroprotection offered by T1AM depends, as for TA1, on AKT activation but do not allow to conclusively indicate TAAR1 as the target implicated. Graphical abstrac

3-iodothyronamine affects thermogenic substrates’ mobilization in brown adipocytes

We investigated the effect of 3-iodothyronamine (T1AM) on thermogenic substrates in brown adipocytes (BAs). BAs isolated from the stromal fraction of rat brown adipose tissue were exposed to an adipogenic medium containing insulin in the absence (M) or in the presence of 20 nM T1AM (M+T1AM) for 6 days. At the end of the treatment, the expression of p-PKA/PKA, p-AKT/AKT, p-AMPK/AMPK, p-CREB/CREB, p-P38/P38, type 1 and 3 beta adrenergic receptors (β1–β3AR), GLUT4, type 2 deiodinase (DIO2), and uncoupling protein 1 (UCP-1) were evaluated. The effects of cell conditioning with T1AM on fatty acid mobilization (basal and adrenergic-mediated), glucose uptake (basal and insulin-mediated), and ATP cell content were also analyzed in both cell populations. When compared to cells not exposed, M+T1AM cells showed increased p-PKA/PKA, p-AKT/AKT, p-CREB/CREB, p-P38/P38, and p-AMPK/AMPK, downregulation of DIO2 and β1AR, and upregulation of glycosylated β3AR, GLUT4, and adiponectin. At basal conditions, glycerol release was higher for M+T1AM cells than M cells, without any significant differences in basal glucose uptake. Notably, in M+T1AM cells, adrenergic agonists failed to activate PKA and lipolysis and to increase ATP level, but the glucose uptake in response to insulin exposure was more pronounced than in M cells. In conclusion, our results suggest that BAs conditioning with T1AM promote a catabolic condition promising to fight obesity and insulin resistance

Study of electrically active defects in epitaxial layers on silicon

Electrically active defects in silicon-based epitaxial layers on silicon substrates have been studied by Deep-Level Transient Spectroscopy (DLTS). Several aspects have been investigated, like, the impact of the pre-epi cleaning conditions and the effect of a post-deposition anneal on the deep-level properties. It is shown that the pre-cleaning thermal budget has a strong influence on the defects at the substrate/epi layer interface. At the same time, a post-deposition Forming Gas Anneal can passivate to a large extent the active defect states. Finally, it is shown that application of a post-deposition anneal increases the out-diffusion of carbon from a Si:C stressor layer into the p-type CZ substrate

European and Mediterranean mercury modelling: local and long-range contributions to the deposition flux

Mercury (Hg) is a global pollutant that is known to have adverse effects on human health, and most human exposure to toxic methylmercury is through fish consumption. Soluble Hg compounds in the marine environment can be methylated in the water column and enter the base of the food chain. Atmospheric deposition is the most important pathway by which Hg enters marine ecosystems. The atmospheric chemistry of Hg has been simulated over Europe and the Mediterranean for the year 2009, using the WRF/Chem model and employing two different gas phase Hg oxidation mechanisms. The contributions to the marine deposition flux from dry deposition, synoptic scale wet deposition and convective wet deposition have been determined. The Hg deposition fluxes resulting from transcontinental transport and local/regional emission sources has been determined using both Br/BrO and O3/OH atmospheric oxidation mechanisms. The two mechanisms give significantly different annual deposition fluxes (129 Mg and 266 Mg respectively) over the modelling domain. Dry deposition is more significant using the O3/OH mechanism, while proportionally convective wet deposition is enhanced using the Br/BrO mechanism. The simulations using the Br/BrO oxidation compared best with observed Hg fluxes in precipitation. Local/regional Hg emissions have the most impact within the model domain during the summer. A comparison of simulations using the 2005 and 2010 AMAP/UNEP Hg emission inventories show that although there is a decrease of 33% in anthropogenic emissions between the two reference years, the total simulated deposition in the regions diminishes by only 12%. Simulations using the 2010 inventory reproduce observations somewhat better than those using the 2005 inventory for 2009

Model study of global mercury deposition from biomass burning

Mercury emissions from biomass burning are not well characterized and can differ significantly from year to year. This study utilizes three recent biomass burning inventories (FINNv1.0, GFEDv3.1, and GFASv1.0) and the global Hg chemistry model, ECHMERIT, to investigate the annual variation of Hg emissions, and the geographical distribution and magnitude of the resulting Hg deposition fluxes. The roles of the Hg/CO enhancement ratio, the emission plume injection height, the Hg(g)0 oxidation mechanism and lifetime, the inventory chosen, and the uncertainties with each were considered. The greatest uncertainties in the total Hg deposition were found to be associated with the Hg/CO enhancement ratio and the emission inventory employed. Deposition flux distributions proved to be more sensitive to the emission inventory and the oxidation mechanism chosen, than all the other model parametrizations. Over 75% of Hg emitted from biomass burning is deposited to the world’s oceans, with the highest fluxes predicted in the North Atlantic and the highest total deposition in the North Pacific. The net effect of biomass burning is to liberate Hg from lower latitudes and disperse it toward higher latitudes where it is eventually deposited

A rare case of solitary fibrous tumour of the pelvis in an 18-year-old young man: Ct and mri features with pathologic correlations

Solitary fibrous tumors (SFTs) are mesenchymal neoplasms of fibroblastic origin, even if commonly seen in the pleura, they can occur anywhere in the body. SFT presents as a slow growing, often asymptomatic mass, generally affecting middle-aged adults regardless of the sex. We report a rare case of an 18-year-old man referred to our institution to perform computed tomography (CT) and magnetic resonance imaging (MRI), to investigate a pelvic mass incidentally discovered at abdominal ultrasound examination. A well circumscribed, heterogenous and hypervascular lesion was described at imaging, with absence of calcifica-tions, hemorrhage, necrosis nor cystic degeneration. The mass removal was performed via the Da Vinci-assisted robotic surgery. Histopathological evaluation confirmed the diagnosis of SFT. CT and MRI can aid the identification of SFT, providing useful information which needs to be supported by histopathological analysis

Angiotensin-II drives human satellite cells toward hypertrophy and myofibroblast trans-differentiation by two independent pathways

Skeletal muscle regeneration is ensured by satellite cells (SC), which upon activation undergo self-renewal and myogenesis. The correct sequence of healing events may be offset by inflammatory and/or fibrotic factors able to promote fibrosis and consequent muscle wasting. Angiotensin-II (Ang) is an effector peptide of the renin angiotensin system (RAS), of which the direct role in human SCs (hSCs) is still controversial. Based on the hypertrophic and fibrogenic effects of Ang via transient receptor potential canonical (TRPC) channels in cardiac and renal tissues, we hypothesized a similar axis in hSCs. Toward this aim, we demonstrated that hSCs respond to acute Ang stimulation, dose-dependently enhancing p-mTOR, p-AKT, p-ERK1/2 and p-P38. Additionally, sub-acute Ang conditioning increased cell size and promoted trans-differentiation into myofibroblasts. To provide a mechanistic hypothesis on TRPC channel involvement in the processes, we proved that TRPC channels mediate a basal calcium entry into hSCs that is stimulated by acute Ang and strongly amplified by sub-chronic Ang conditioning. Altogether, these findings demonstrate that Ang induces a fate shift of hSCs into myofibroblasts and provide a basis to support a benefit of RAS and TRPC channel blockade to oppose muscle fibrosis

Tisochrysis lutea F&M-M36 Mitigates Risk Factors of Metabolic Syndrome and Promotes Visceral Fat Browning through β3-Adrenergic Receptor/UCP1 Signaling

Pre-metabolic syndrome (pre-MetS) may represent the best transition phase to start treatments aimed at reducing cardiometabolic risk factors of MetS. In this study, we investigated the effects of the marine microalga Tisochrysis lutea F&M-M36 (T. lutea) on cardiometabolic components of pre-MetS and its underlying mechanisms. Rats were fed a standard (5% fat) or a high-fat diet (20% fat) supplemented or not with 5% of T. lutea or fenofibrate (100 mg/Kg) for 3 months. Like fenofibrate, T. lutea decreased blood triglycerides (p < 0.01) and glucose levels (p < 0.01), increased fecal lipid excretion (p < 0.05) and adiponectin (p < 0.001) without affecting weight gain. Unlike fenofibrate, T. lutea did not increase liver weight and steatosis, reduced renal fat (p < 0.05), diastolic (p < 0.05) and mean arterial pressure (p < 0.05). In visceral adipose tissue (VAT), T. lutea, but not fenofibrate, increased the β3-adrenergic receptor (β3ADR) (p < 0.05) and Uncoupling protein 1 (UCP-1) (p < 0.001) while both induced glucagon-like peptide-1 receptor (GLP1R) protein expression (p < 0.001) and decreased interleukin (IL)-6 and IL-1β gene expression (p < 0.05). Pathway analysis on VAT whole-gene expression profiles showed that T. lutea up-regulated energy-metabolism-related genes and down-regulated inflammatory and autophagy pathways. The multitarget activity of T. lutea suggests that this microalga could be useful in mitigating risk factors of MetS

Sensitivity model study of regional mercury dispersion in the atmosphere

Atmospheric deposition is the most important pathway by which Hg reaches marine ecosystems, where it can be methylated and enter the base of food chain. The deposition, transport and chemical interactions of atmospheric Hg have been simulated over Europe for the year 2013 in the framework of the Global Mercury Observation System (GMOS) project, performing 14 different model sensitivity tests using two high-resolution three-dimensional chemical transport models (CTMs), varying the anthropogenic emission datasets, atmospheric Br input fields, Hg oxidation schemes and modelling domain boundary condition input. Sensitivity simulation results were compared with observations from 28 monitoring sites in Europe to assess model performance and particularly to analyse the influence of anthropogenic emission speciation and the Hg0(g) atmospheric oxidation mechanism. The contribution of anthropogenic Hg emissions, their speciation and vertical distribution are crucial to the simulated concentration and deposition fields, as is also the choice of Hg0(g) oxidation pathway. The areas most sensitive to changes in Hg emission speciation and the emission vertical distribution are those near major sources, but also the Aegean and the Black seas, the English Channel, the Skagerrak Strait and the northern German coast. Considerable influence was found also evident over the Mediterranean, the North Sea and Baltic Sea and some influence is seen over continental Europe, while this difference is least over the north-western part of the modelling domain, which includes the Norwegian Sea and Iceland. The Br oxidation pathway produces more HgII(g) in the lower model levels, but overall wet deposition is lower in comparison to the simulations which employ an O3 ∕ OH oxidation mechanism. The necessity to perform continuous measurements of speciated Hg and to investigate the local impacts of Hg emissions and deposition, as well as interactions dependent on land use and vegetation, forests, peat bogs, etc., is highlighted in this study