IL-10 Signaling Remodels Adipose Chromatin Architecture to Limit Thermogenesis and Energy Expenditure

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<Emphasis Type="Italic">Trans</Emphasis>-cinnamaldehyde Modulates Hippocampal Nrf2 Factor and Inhibits Amyloid Beta Aggregation in LPS-Induced Neuroinflammation Mouse Model

Trans-cinnamaldehyde (CNM) has recently drawn attention due to its potent anti-inflammatory and antioxidant properties. The current study explored the memory enhancing effects of CNM against lipopolysaccharide (LPS)-induced neuroinflammation in mice. CNM and curcumin (a reference antioxidant) were administered at a dose of 50 mg/kg i.p. 3 h after a single LPS injection (0.8 mg/kg, i.p.) and continued daily for 7 days. Our results displayed that CNM and curcumin significantly ameliorated the LPS-induced impairment of learning and memory, neuroinflammation, oxidative stress and neuronal apoptosis. Memory functions and locomotor activity were assessed by Morris water maze, object recognition test and open field test. Both CNM and curcumin activated the nuclear factor erythroid 2 related factor 2 (Nrf2) and restored levels of downstream antioxidant enzymes superoxide dismutase and glutathione-S-transferase (GST) in the hippocampus. They also attenuated LPS-induced increase in hippocampal contents of interleukin-1β (IL-1β), malondialdehyde and caspase-3. Immunohistochemistry results showed that both CNM and curcumin reduced Aβ_1–42 protein accumulation in brain of mice. Remarkably CNM’s effect on IL-1β was less pronounced than curcumin; however it showed higher GST activity and more potent anti-apoptotic and anti-amylodogenic effect. We conclude that, CNM produces its memory enhancing effects through modulation of Nrf2 antioxidant defense in hippocampus, inhibition of neuroinflammation, apoptosis and amyloid protein burden.     

Comparative Modeling and Evaluation of Leukotriene B4 Receptors for Selective Drug Discovery Towards the Treatment of Inflammatory Diseases

Leukotriene B4 (LTB4) exerts its biological effects through stimulation of specific G protein-coupled receptors (GPCRs)—namely BLT1 and BLT2. Due to the absence of human BLT1 and BLT2 crystal structures, the current study was set to predict the 3D structures of these two receptors for structure-based anti-inflammatory drug discovery. Homology modeling of the BLT1 receptor was first constructed, based on various X-ray and NMR GPCR templates, followed by molecular dynamics (MD) refinement. Using a single-template approach, nine well-established alignment methods and ten secondary structure prediction methods during the backbone generation were implemented and assessed. The binding sites of the BLT1 receptor were then mapped using fifteen chemical probes with the help of FTMAP and AutoDock Vina 4.2 software. Model validation was performed through the docking of eight specific antagonists that have experimental inhibition constants (k_i) towards BLT1. The antagonists-BLT1 docked structures were then subjected to AMBER-based molecular mechanical minimization and the corresponding binding energies were calculated using molecular mechanics–generalized Born surface area (MM/GBSA) approach. According to the results, the most energetically stable models were constructed using SAlign method for the alignment process and PSIPRED for secondary structure prediction. In comparison, the refined BLT1 model built on 2KS9 as an NMR template has the lowest DOPE energy compared to those built on 4EA3 and 4XT1 as X-ray templates. According to the mapping results, two main binding sites were identified: one was among TMs II, III and VII and the other was among TMs III, IV and V. For the antagonists, correlation between binding energies and experimental data was in a good agreement, with a correlation coefficient (R² value) of 0.91. Due to the great amino acid sequence similarity between BLT1 and BLT2 receptors (calculated as 45.2%), BLT2 model was constructed based on the predicted BLT1 model.     

In Silico and Experimental Data Claiming Safety Aspects and Beneficial Attributes of the Bacteriocinogenic Strain <Emphasis Type="Italic">Enterococcus faecalis</Emphasis> B3A-B3B

This study aimed at comparing the genome of Enterococcus faecalis B3A-B3B, a bacteriocinogenic strain recently isolated from a healthy Iraqi infant to those of Enterococci of clinical and beneficial grades. The putative genes gelE, cpd, efaAfm, ccf, agg, and cob coding for virulence factors were detected in B3A-B3B strain, which meanwhile resulted to be non-cytotoxic, non-hemolytic, devoid of inflammatory effects, and sensitive to most of the antibiotics tested except for clindamycin and trimethoprim, which resistance is usually ascribed to intrinsic nature. B3A-B3B strain was remarkable for its hydrophobicity, auto-aggregation, adhesion to human Caco-2 cells, and survival in simulated gastrointestinal conditions, and cholesterol assimilation fulfilling therefore key beneficial attributes.     

An oral cancer biobank initiative: a platform for multidisciplinary research in a developing country

Identification of diagnostic markers for early detection and development of novel and therapeutic agents for effective patient management are the main motivation for cancer research. Biological specimens from large cohort and case-control studies which are crucial in providing successful research outcomes are often the limiting factor that hinders research efforts, especially in developing countries. Therefore, the Malaysian Oral Cancer Database and Tissue Bank System (MOCDTBS) were established to systematically collect large number of samples with comprehensive sociodemographic, clinicopathological, management strategies, quality of life and associated patient follow-up data to facilitate oral cancer research in Malaysia. The MOCDTBS also promotes sharing among researchers and the development of a multidisciplinary research team. The following article aims to describe the process of setting-up and managing the MOCDTBS.     

Studies ON Epimeric-D-asabino-and-D-ribo-tetritol-1-yl-2-phenyl-2 H-1,2,3-triazoles. Synthesis and Anomeric Configuration of 4-(α-and β-D-Erythrofuranosyl)-2-phenyl-2 H-1,2,3-Triazole C-Nucleoside Analogs

Abstract

Treatment of 4-(D-arabino-tetritol-1-yl)-2-phenyl-2 H-1,2,3-triazole (1) with one mole equivalent of tosyl chloride in pyridine solution, afforded the C-nucleoside analogs, 4-(α-D-erythrofuranosyl)-2-phenyl-2 H-1,2,3-triazole (2) in 25% yield, as well as the byproduct 4-(4-chloro-4-deoxy-D-arabino-tetritol-1-yl)-2-phenyl-2 H-1,2,3-triazole(3). Treatment of the epimeric 4-(D-ribo-tetritol-1-yl)-2-phenyl-2 H-1,2,3-triazole(8) with tosyl chloride in pyridine solution afforded the anomeric C-nucleoside analogs, 4-(β-D-erythrofuranosyl)-2-phenyl-2 H-1,2,3-triazole (9) in 23% yield. Similar treatment of 8 with trifluoromethanesulfonyl chloride in pyridine solution afforded 9. The structure and anomeric configuration of these compounds were determined by acylation, NMR, NOE, circular dichroism spectroscopy and mass spectrometry.     

Molecular design,synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2

A group of cyclic imides (1–10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC₅₀ range of 0.1–4.0 μM. In vitro COX-1/COX-2 inhibition structure–activity studies identified compound 8a as a highly potent (IC₅₀ = 0.1 μM), and an extremely selective [COX-2 (SI) > 1000] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED₅₀ = 72.4 mg/kg) relative to diclofenac (ED₅₀ = 114 mg/kg). Molecular modeling was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO₂NH₂ group underwent H-bonding interaction with Gln¹⁹²(2.95 Å), Phe⁵¹⁸(2.82 Å) and Arg⁵¹³(2.63 and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.     

Ghrelin improves burn-induced delayed gastrointestinal transit in rats

Delayed gastrointestinal transit is common in patients with severe burn. Ghrelin is a potent prokinetic peptide. We aimed at testing the effect of ghrelin on burn-induced delayed gastrointestinal transit in rats. Gastric emptying (GE), intestinal transit (IT), and colonic transit (CT) studies were performed in male Sprague-Dawley rats. Rats were randomized into two main groups as follows: sham injury and ghrelin-treated burn injury with doses of 0, 2, 5, and 10 nmol/rat ip 6 h after burn. Sham/burn injury was induced under anesthesia. Rats received a phenol red meal 20 min following ghrelin injection. Based on the most effective ghrelin dose, 1 mg/kg sc atropine was given 30 min before the ghrelin in one group of rats for each study. The rats in each group were killed 30-90 min later; their stomachs, intestines, and colons were harvested immediately, and the amount of phenol red recovered was measured. Percentage of gastric emptying (GE%) and geometric center for IT and CT were calculated. We found 1) severe cutaneous burn injury significantly delayed GE, IT, and CT compared with sham injury (P < 0.05); 2) ghrelin normalized both GE and IT, but not the CT; 3) the most effective dose of ghrelin was 2 nmol/rat; and 4) atropine blocked the prokinetic effects of ghrelin on GE% and IT. In conclusion, ghrelin normalizes burn-induced delayed GE and IT but has no effect on CT in rats. The prokinetic effects of ghrelin are exerted via the cholinergic pathway. Ghrelin may have a therapeutic potential for burn patients with delayed upper gastrointestinal transit.     

A crystal-clear interaction: relating neuroligin/neurexin complex structure to function at the synapse

Neuronal circuits are maintained by homeostatic mechanisms controlling synapse maturation and signaling. Neuroligins (NLs) and neurexins (Nrxs) may regulate the fine balance between excitation and inhibition. In this issue of Neuron, Ara? et al. and Fabrichny et al. define crystal structures of NLs bound to beta-Nrx, providing insights into their synaptic actions and clarifying structural defects associated with autism-linked mutations.     

Design,synthesis, and analysis of antiproliferative and apoptosis-inducing activities of nitrile derivatives containing a benzofuran scaffold: EGFR inhibition assay and molecular modelling study

New cyanobenzofurans derivatives 2–12 were synthesised, and their antiproliferative activity was examined compared to doxorubicin and Afatinib (IC₅₀ = 4.17–8.87 and 5.5–11.2 µM, respectively). Compounds 2 and 8 exhibited broad-spectrum activity against HePG2 (IC₅₀ = 16.08–23.67 µM), HCT-116 (IC₅₀ = 8.81–13.85 µM), and MCF-7 (IC₅₀ = 8.36–17.28 µM) cell lines. Compounds 2, 3, 8, 10, and 11 were tested as EGFR-TK inhibitors to demonstrate their possible anti-tumour mechanism compared to gefitinib (IC₅₀ = 0.90 µM). Compounds 2, 3, 10, and 11 displayed significant EGFR TK inhibitory activity with IC₅₀ of 0.81–1.12 µM. Compounds 3 and 11 induced apoptosis at the Pre-G phase and cell cycle arrest at the G2/M phase. They also increased the level of caspase-3 by 5.7- and 7.3-fold, respectively. The molecular docking analysis of compounds 2, 3, 10, and 11 indicated that they could bind to the active site of EGFR TK.