Amber force field implementation, molecular modelling study, synthesis and MMP-1/MMP-2 inhibition profile of (R)- and (S)-N-hydroxy-2-(N-isopropoxybiphenyl-4-ylsulfonamido)-3-methylbutanamides

Ab initio calculations (B3LYP/Lanl2DZ level of theory) were performed in this study to determine all the structural and catalytic zinc parameters required in order to study MMPs and their complexes with hydroxamate inhibitors by means of the AMBER force field. The parameters thus obtained were used in order to study the docking of some known MMPi (Batimastat, CGS 27023A and Prinomastat) and our previously described inhibitor a which had shown an inhibitory activity for MMP-1, and -2, with the aim of explaining the different selectivity. On this basis the two enantiomers (R)-b and (S)-b were designed and synthesized, as more potent MMP-2 inhibitors than our previously described inhibitor a. Between these two enantiomers the eutomer (R)-b proved to be 24.7 times and 15.3 times more potent than CGS 27023A and the parent compound a on MMP-2, maintaining a higher index of MMP-2/MMP-1 selectivity compared with CGS 27023A and the more potent inhibitor Prinomastat. The hydroxamate (R)-b can be considered as a progenitor of a new class of biphenylsulfonamido-based inhibitors that differ from compound a in the presence of an alkyl side chain on the C alpha atom, and show different potency and selectivity profiles on the two MMPs considered.     

Cytosine-block telomeric type DNA-binding activity of hnRNP proteins from human cell lines

Following the observation of the presence in mammalian nuclear extracts of a DNA binding activity quite specific for the single-stranded C-rich telomeric motif, we have isolated from the K562 human cell line by affinity chromatography and identified by mass spectrometry a number of proteins able to bind to this sequence. All of them belong to different heterogeneous nuclear ribonucleoprotein subgroups (hnRNP). Whereas many of them, namely hnRNP K, two isoforms of hnRNP I, and the factor JKTBP, appear to bind to this sequence with limited specificity after isolation, an isoform of hnRNP D (alias AUF1) and particularly hnRNP E1 (alias PCBP-1) show a remarkable specificity for the (CCCTAA)n repeated motif. Both have been obtained also as recombinant proteins expressed in Escherichia coli and have been shown to retain their binding specificity toward the C-block repeated sequence. In the light of the current knowledge about these proteins, their possible involvement in telomere functioning is discussed.     

Optimization of pyrazole inhibitors of Coactivator Associated Arginine Methyltransferase 1 (CARM1)

Design, synthesis, and SAR development led to the identification of the potent, novel, and selective pyrazole based inhibitor (7f) of Coactivator Associated Arginine Methyltransferase (CARM1).     

Mass loss and macroinvertebrate colonisation of fish carcasses in riffles and pools of a NW Italian stream

In this study, we analysed the decomposition of trout carcasses in a low-order Apennine stream, with the aim to investigate the mass loss rate in a Mediterranean lotic system, and to examine the influence of microhabitats on the invertebrates colonising fish carcasses. In May 2003, we put 56 dead rainbow trout (Oncorhynchus mykiss) in the stream, placing seven sets (four trout each) in both riffle and pool habitats. At four dates, we removed one trout per set to measure its dry mass and determine the associated macroinvertebrate assemblage. Fifty-eight macroinvertebrate taxa colonised the carcasses, with significant differences between the erosive and depositional microhabitats. Riffle trouts hosted richer and denser colonist communities than pool trouts. Chironomidae, Serratella ignita, Habrophlebia sp., Dugesia sp. and Protonemura sp. were the five most abundant taxa. Decomposition was initially very rapid in both environments and then tapered off over time. The mass loss rate was higher (k= –0.057 day^–1) than that found in other studies. Higher Mediterranean temperatures probably increase the process. Although we found no significant difference between riffles and pools, mass loss was more regular in erosive habitats, underlining the importance of local, small-scale conditions. In small, low-order, heterotrophic streams, fish carcasses represent an important resource and shelter for rich and diversified invertebrate assemblages.     

Caffeine Impairs Myocardial Blood Flow Response to Physical Exercise in Patients with Coronary Artery Disease as well as in Age-Matched Controls

Background

Caffeine is one of the most widely consumed pharmacologically active substances. Its acute effect on myocardial blood flow is widely unknown. Our aim was to assess the acute effect of caffeine in a dose corresponding to two cups of coffee on myocardial blood flow (MBF) in coronary artery disease (CAD).

Methodology/Principal Findings

MBF was measured with ¹⁵O-labelled H2O and Positron Emission Tomography (PET) at rest and after supine bicycle exercise in controls (n = 15, mean age 58±13 years) and in CAD patients (n = 15, mean age 61±9 years). In the latter, regional MBF was assessed in segments subtended by stenotic and remote coronary arteries. All measurements were repeated fifty minutes after oral caffeine ingestion (200 mg). Myocardial perfusion reserve (MPR) was calculated as ratio of MBF during bicycle stress divided by MBF at rest. Resting MBF was not affected by caffeine in both groups. Exercise-induced MBF response decreased significantly after caffeine in controls (2.26±0.56 vs. 2.02±0.56, P<0.005), remote (2.40±0.70 vs. 1.78±0.46, P<0.001) and in stenotic segments (1.90±0.41 vs. 1.38±0.30, P<0.001). Caffeine decreased MPR significantly by 14% in controls (P<0.05 vs. baseline). In CAD patients MPR decreased by 18% (P<0.05 vs. baseline) in remote and by 25% in stenotic segments (P<0.01 vs. baseline).

Conclusions

We conclude that caffeine impairs exercise-induced hyperaemic MBF response in patients with CAD to a greater degree than age-matched controls.     

Microhabitat preference of sympatric Hydraena Kugelann, 1794 species (Coleoptera: Hydraenidae) in a low-order forest stream

Aim of this study was to investigate the presence and distribution of Hydraenidae in relation to selected abiotic parameters in a single, uniform riffle of the Caramagna Stream (northwestern Italy). Six species belonging to the genus of Hydraena Kugelann, 1794 were found (H. andreinii D'Orchymont, 1934, H. subimpressa Rey, 1885, H. assimilis Rey, 1885, H. heterogyna Bedel, 1898, H. truncata Rey, 1884 and H. devillei Ganglbauer, 1901), with evident niche preferences. Our study provided interesting information about ecological requirements of minute moss beetles at small-scale and evidenced that maintaining elevate habitat diversity is essential to preserve high species abundance at local scale.     

MicroRNAs expression profiles as diagnostic biomarkers of gastric cancer: a systematic literature review

Objective: The early identification of gastric cancer (GC) represents a major clinical challenge. We conducted a systematic review of studies evaluating the miRNA expression profiling as a diagnostic tool in GC.

Methods: We performed a search of PubMed, ISI Web of Science and SCOPUS databases for studies on diagnostic miRNAs and GC, published in English up to October 2017. Eligibility criteria included case-control studies evaluating blood or tissue-based miRNA expression profiles, and incorporating at least two detection phases (screening and validation).

Results: We included 27 eligible studies, that reported on 97 deregulated miRNAs either in blood or tissue, out of which 30 were reported in at least two studies. Among 22 studies on tissue-diagnostic miRNAs, 13 consistently upregulated miRNAs (miR-214, miR-21, miR-103, miR-107, miR-196a, miR-196b, miR-7, miR-135b, miR-222, miR-23b, miR-25, miR-92 and miR-93), and six consistently downregulated miRNAs (miR-148a, miR-375, miR-133b, miR-30a, miR-193a and miR-204) were reported. Ten miRNAs with inconsistent direction of expression in tissues were identified. Among the five studies performed on blood samples, only one miRNA was consistently upregulated (miR-20a).

Conclusions: This review shows that some tissue or blood miRNAs may be considered as potential biomarkers for GC diagnosis, that urgently needs to be confirmed from large prospective studies.