Synthesis and pharmacological characterization of benzenesulfonamides as dual species inhibitors of human and murine mPGES-1

The microsomal prostaglandin E₂ synthase 1 (mPGES-1) became a desirable target in recent years for the research of new anti-inflammatory drugs. Even though many potent inhibitors of human mPGES-1, tested in vitro assay systems, have been synthesized, they all failed in preclinical trials in rodent models of inflammation, due to the lack of activity on rodent enzyme. Within this work we want to present a new class of mPGES-1 inhibitors derived from a benzenesulfonamide scaffold with inhibitory potency on human and murine mPGES-1. Starting point with an IC₅₀ of 13.8 μM on human mPGES-1 was compound 1 (4-{benzyl[(4-methoxyphenyl)methyl]sulfamoyl}benzoic acid; FR4), which was discovered by a virtual screening approach. Optimization during a structure–activity relationship (SAR) process leads to compound 28 (4-[(cyclohexylmethyl)[(4-phenylphenyl)methyl]sulfamoyl]benzoic acid) with an improved IC₅₀ of 0.8 μM on human mPGES-1. For the most promising compounds a broad pharmacological characterization has been carried out to estimate their anti-inflammatory potential.     

A histological study of the organogenesis of the digestive system in bay snook Petenia splendida Günther, 1862 from hatching to the juvenile stage

In bay snook (Petenia splendida) larvae the histological development of the digestive system and swim bladder, and their relative timing of differentiation were studied from hatching to 45 days post‐hatch (dph) at 29°C. Newly hatched larvae showed a simple digestive tract, which appeared as a straight undifferentiated tube lined by a single layer of columnar epithelial cells (future enterocytes). The anatomical and histological differentiation of the digestive tract and accessory glands was a very intense, asynchronous process, proceeding from the distal to the anterior part. The intestine was the first region to differentiate (9 days post‐hatch – dph, 6.5 mm SL), and the oesophagus the last (21 dph, 8.4 mm SL). At the onset of feeding, the digestive system was organized into different functional and histologically differentiated sections, such as the buccopharynx, oesophagus, glandular stomach, and anterior and posterior intestine. This organization resembled that of the juveniles, with the exception of pharyngeal teeth and buccopharyngeal as well as oesophageal goblet cells, which proliferated later during the mixed feeding period. Histological observations revealed that bay snook larvae retained endogenous yolk reserves until 24 dph (8.9 ± 0.4 mm SL), which might be helpful for weaning this species onto a compound diet. The important lipidic accumulation observed in the intestinal mucosa, liver, and pancreas in fish fed a compound trout diet indicated that although fish were able to digest and absorb lipids, the diet formulation did not fit the nutritional requirements of early juveniles of this species. The ontogeny of the digestive system followed the same general pattern as in most cichlid species described to date. However, we detected species‐specific differences in the timing of differentiation that were related to their reproductive guild. According to the histological results, some recommendations regarding the intensive culture of this species are also provided.     

A2A adenosine receptor ligand binding and signalling is allosterically modulated by adenosine deaminase

A2ARs (adenosine A2A receptors) are highly enriched in the striatum, which is the main motor control CNS (central nervous system) area. BRET (bioluminescence resonance energy transfer) assays showed that A2AR homomers may act as cell-surface ADA (adenosine deaminase; EC 3.5.4.4)-binding proteins. ADA binding affected the quaternary structure of A2ARs present on the cell surface. ADA binding to adenosine A2ARs increased both agonist and antagonist affinity on ligand binding to striatal membranes where these proteins are co-expressed. ADA also increased receptor-mediated ERK1/2 (extracellular-signal-regulated kinase 1/2) phosphorylation. Collectively, the results of the present study show that ADA, apart from regulating the concentration of extracellular adenosine, may behave as an allosteric modulator that markedly enhances ligand affinity and receptor function. This powerful regulation may have implications for the physiology and pharmacology of neuronal A2ARs.     

Prolonged feed deprivation does not permanently compromise digestive function in migrating European glass eels Anguilla anguilla

The effects of prolonged feed deprivation (40 days at 18° C) and re-feeding (30 days) on body mass, growth and the activity of selected pancreatic and intestinal enzymes were evaluated in migrating European glass eels Anguilla anguilla by comparison with a control group fed to satiation with hake Merluccius merluccius roe for the duration of the experiment. Feed deprivation resulted in mass loss and a reduction in digestive function, as revealed by a decrease in the total and specific activities of pancreatic (trypsin and α-amylase) and intestinal brush border (alkaline phosphatase and leucine aminopeptidase) enzymes. The total activity of intestinal brush border enzymes diminished after 5 days of feed deprivation, whereas that of pancreatic enzymes did not decrease until 10 days, indicating that the intestine is more sensitive to feed deprivation than the pancreas. Re-feeding A. anguilla that were starved for 40 days resulted in compensatory growth, with specific growth rates that were 2·6 times higher than the control group. This compensatory growth was associated with the recovery of trypsin and intestinal brush border enzyme activities, which were restored to control levels within 5 days of re-feeding. The ability to maintain pancreatic enzyme activity during 40 days of feed deprivation, and rapidly recover capacity for protein digestion upon re-feeding, would enable A. anguilla at this glass eel stage to withstand periods without food but rapidly provide amino acids for protein synthesis and growth when suitable food was available.     

Signalling through kinase-defective domains: the prevalence of atypical receptor-like kinases in plants

The structure of plant receptor-like kinases (RLKs) is similar to that of animal receptor tyrosine kinases (RTKs), and consists of an extracellular domain, a transmembrane span, and a cytoplasmic domain containing the conserved kinase domain. The mechanism by which animal RTKs, and probably plant RLKs, signal includes the dimerization of the receptor, their intermolecular phosphorylation, and the phosphorylation of downstream signalling proteins. However, atypical RTKs with a kinase-dead domain that signal through phosphorylation-independent mechanisms have also been described in animals. In the last few years, some atypical RLKs have also been reported in plants. Here these examples and their possible signalling mechanisms are reviewed. Plant genomes contain a much larger number of genes coding for receptor kinases than other organisms. The prevalence of atypical RLKs in plants is analysed here. A sequence analysis of the Arabidopsis kinome revealed that 13% of the kinase genes do not retain some of the residues that are considered as invariant within kinase catalytic domains, and are thus putatively kinase-defective. This percentage rises to close to 20% when analysing RLKs, suggesting that phosphorylation-independent mechanisms mediated by atypical RLKs are particularly important for signal transduction in plants.     

13C-urea breath test during hospitalization for the diagnosis of Helicobacter pylori infection in peptic ulcer bleeding

Objective: To evaluate the accuracy of ¹³C‐urea breath test (UBT) to detect Helicobacter pylori infection in patients hospitalized with peptic ulcer bleeding and treated with proton pump inhibitors (PPIs). Methods: Patients hospitalized with peptic ulcer bleeding, and treated with omeprazole, had a first UBT performed the day after resuming oral feeding. Patients with a negative UBT during hospitalization underwent a repeated UBT 15 days after stopping PPIs. Results: The first UBT during hospitalization was positive in 86% of 131 patients. Time between admission and performance of the test was longer in patients with negative versus positive UBT (5.2 ± 0.7 versus 4.3 ± 0.5 days; p < .001). The repeated UBT became positive in 15 of 18 (83%) patients with a negative first UBT. In the multivariate analysis, the only variable associated with a negative first UBT was the time elapsed between admission and performance of the test (odds ratio = 6.6; 95%CI = 2.9–15.1). Conclusion: Most H. pylori‐positive patients with ulcer bleeding have a positive UBT (performed just after resuming oral feeding) despite previous treatment with high‐dose PPIs. Nevertheless, to preclude false‐negative results due to PPI therapy, the UBT should be performed as early as possible. If the infection cannot be demonstrated with this first UBT, H. pylori still needs to be definitively excluded with a second UBT performed after stopping PPIs.     

Effects of different dietary levels of fish protein hydrolysates on growth, digestive enzymes, gut microbiota, and resistance to Vibrio anguillarum in European sea bass (Dicentrarchus labrax) larvae

Two fish protein hydrolysates (FPH) were incorporated into four diets prepared for start-feeding sea bass larvae, at two different levels (10% and 19% of total ingredients): a commercial FPH, CPSP, in which the molecular mass of the main fraction of soluble peptides (51%) was between 500-2500 Da, and an experimental FPH obtained by acidic silage of sardine offal, SH, with a main portion of soluble peptides (54%) ranging from 200 to 500 Da. The diet with 10% of the commercial FPH gave the best results in terms of growth, survival and intestinal development, as evaluated by the early activity of digestive enzymes in the brush border membrane (alkaline phosphatase and aminopeptidase N). This was related to the low level of Vibrio spp. counted in the larvae of group C10. The high dose of FPH, especially in the experimental preparation rich in short peptides, seemed to favour the dominance of Vibrio sp. TYH3, which behaved opportunistically. The effect of the experimental FPH was ambiguous, since early larvae challenged with Vibrio anguillarum were more resistant to the pathogen, especially at high FPH dose (group S19). This might be due either to direct antagonism between V. anguillarum and Vibrio sp. TYH3, or to the stimulation of the immune response in the larvae. These results indicate that different molecular weight fractions and concentrations of feed-soluble peptides may affect the growth performance and immunological status of sea bass larvae. Consequently, a low dose of commercial FPH seems advisable, both for larval development and for the bacterial environment, although further research is required to determine and characterize peptide fractions that may have a beneficial effect on growth and immune response, and to determine their optimal inclusion levels in diets for sea bass larvae.     

Emergent freeze and fire disturbance dynamics in temperate rainforests

The coastal temperate rainforests of South and North America are part of the most biomass dense forest biome on the planet. They are also subject to rapid climatic shifts and, subsequently, new disturbance processes – snow loss‐driven mortality and the emergence of fire in historically non‐fire‐exposed areas. Here, we compare and contrast Southern and Northern Hemisphere coastal temperate rainforests of the Americas, two of the largest examples of the biome, via synthesis of current literature, future climate expectations and new downscaling of a global fire model. In terms of snow loss, a rapid decline in winter snow is leading to mass mortality of certain conifer species in the Northern Hemisphere rainforests. High‐elevation Southern Hemisphere forests, which are beginning to see similar declines in snow, may be vulnerable in the future, especially bogs and high‐water content soils. Southern Hemisphere forests are seeing the invasion of fire as an ecological force at mid‐to‐high latitudes, a shift not yet observed in the north but which may become more prominent with ongoing climate change. We suggest that research should focus on the flammability of seral vegetation and bogs under future climate scenarios in both regions. By comparing these two drivers of change across similar gradients in the Northern and Southern Hemispheres, this work points to the potential for emerging change in unexpected places in both regions. There is a clear benefit to conceptualising the coastal temperate rainforests of the Americas as two examples of the biome which can inform the other, as change is proceeding in similar directions but at different rates in each region.