A micro RNA processing defect in rapidly progressing idiopathic pulmonary fibrosis

Background

Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF.

Methodology and Principal Findings

miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts.

Conclusion

These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing.     

Headspace analyses of H labeling of acetone: Enabling studies of fatty acid oxidation in vivo

We demonstrate that one can measure low levels of ²H labeling (e.g., <0.025% excess ²H) by exchanging hydrogen (deuterium) in water with acetone and subjecting samples to gas chromatography–pyrolysis–isotope ratio mass spectrometry. This analytical method circumvents the need to use typical off-line reduction methods that convert water to hydrogen gas prior to isotope ratio mass spectrometry or the need to purchase extra peripheral devices that would permit the direct analysis of water labeling. This method enables routine measurements of fatty acid oxidation in rodents; that is, one administers a ²H-labeled fatty acid(s) and then quantifies the production of ²H-labeled water.     

Synthesis and antifungal evaluation of pentyloxyl-diphenylisoxazoloyl pneumocandins and echinocandins

Echinocandins and pneumocandins are classes of lipocyclohexapeptides that are broad spectrum antifungal agents. They inhibit fungal specific 1,3-β-glucan synthase activity which is an essential component of the fungal cell wall. Chemical modifications of these two leads have produced three clinical agents namely caspofungin, micafungin and anidulafungin. The presence of hydroxy-glutamine versus threonine and unsaturated linear fatty acid versus branched chain saturated fatty acid differentiate the two classes of compounds with profound differences in their hemolytic properties. In the current study, we have replaced the side chain of the cyclohexapeptides with a common aromatic heterocyclic acyl side chain and compared the biological activities of the cores head-to-head and for the first time demonstrated the role played by the acyl chain and the hydroxy-glutamine for the antifungal potency.     

The use of stable-isotopically labeled oleic acid to interrogate lipid assembly in vivo: assessing pharmacological effects in preclinical species

The use of stable isotopically labeled substrates and analysis by mass spectrometry have provided substantial insight into rates of synthesis, disposition, and utilization of lipids in vivo. The information to be gained from such studies is of particular benefit to therapeutic research where the underlying causes of disease may be related to the production and utilization of lipids. When studying biology through the use of isotope tracers, care must be exercised in interpreting the data to ensure that any response observed can truly be interpreted as biological and not as an artifact of the experimental design or a dilutional effect on the isotope. We studied the effects of dosing route and tracer concentration on the mass isotopomer distribution profile as well as the action of selective inhibitors of microsomal tri-glyceride transfer protein (MTP) in mice and diacylglycerol acyltransferase 1 (DGAT1) in nonhuman primates, using a stable-isotopically labeled approach. Subjects were treated with inhibitor and subsequently given a dose of uniformly 13C-labeled oleic acid. Samples were analyzed using a rapid LC-MS technique, allowing the effects of the intervention on the assembly and disposition of triglycerides, cholesteryl esters, and phospholipids to be determined in a single 3 min run from just 10 μl of plasma.     

A new sesquiterpene lactone from Elephantopus scaber

A methanolic extract of the plant Elephantopus scaber was found to contain lupeol, stigmasterol and a new germacranolide dilactone 11,13-dihydrodeoxyelephantopin.     

Temperature effects on the response to sulphur of barley,peas and rape

Summary The effects of temperature and sulphur nutrition on the growth, yield and mineral composition (N, NO₃-N, S and SO₄-S) ofHordeum vulgare L. cv Olli,Pisum sativum L. cv Dark Skin Perfection, andBrassica campestris L. cv Arlo, were investigated in controlled environments. When barley and rape plants were grown at O ppm S, deficiency symptoms developed in about two weeks, whereas peas at the same level developed deficiency symptoms in about three weeks. The location of the deficiency symptoms varied between species. Plant weight increased with increasing S levels, but the shoot had a greater growth response than did the root. Optimum day/night growing temperature regimes for barley and peas were found to be near 24/16 at four weeks from seeding and near 18/10°C at the mature stage as evident from weights, maximum fruit set and mineral uptake. Optimum temperature for rape plants was near 29/21°C at both stages of growth. Mineral concentration was higher at four weeks after seeding than at the mature stage in pea and rape plants, while in barley the mineral concentration was similar at both stages of growth. With increase in S supply there was an increase in concentration of both total S and SO₄-S. Concentrations also increased with increasing temperatures. S deficient plants had increased total N and NO₃-N concentrations in all three species. NO₃-N concentration also increased with an increase in temperature while total N concentration was not appreciably influenced. These experiments indicated that the effects of S nutrition on growth, development and mineral composition of plants depends on the species, temperature regime and growth stage     

Bergenin: a computationally proven promising scaffold for novel galectin-3 inhibitors

Bergenin is a C-glycoside of 4-O-methylgallic acid that is isolated from medicinal plants such as Flueggea leucopyrus, Bergenia crassifolia, Mallotus philippensis, Corylopsis spicata, Caesalpinia digyna, Mallotus japonicus, and Sacoglottis gabonensis. Even though there appears to be ample evidence from South Asian traditional medicine that bergenin possesses strong anticancer activity, no comprehensive scientific study has been carried out to test its anticancer potency. Therefore, in this study, the potential mechanisms of action for bergenin’s postulated anticancer activity were examined using computational techniques. Firstly, bergenin was tested for its toxicity as a drug candidate using in silico toxicity analysis. It was found that bergenin is nontoxic according to modern toxicity measures. The optimized structure of bergenin was obtained at the DFT-B3LYP/6-31G(d) level of theory. Potential biological targets of bergenin were identified using reverse docking calculations. Reverse docking results suggested that galectin-3 is a potential target of bergenin. Gelectin-3 is an enzyme that plays a major role in cell–cell adhesion, cell-matrix interactions, macrophage activation, angiogenesis, metastasis, and apoptosis in cancer, making it a popular target in anticancer drug design. Among the many potential biological targets predicted by reverse docking calculations, galectin-3 was selected as it complies with the primary objective of this study. The binding of bergenin to galectin-3 was studied by conventional forward docking calculations. Classical molecular dynamics (MD) simulations were used to study the stability of the galectin-3:bergenin complex. Docking calculations indicated that bergenin has the potential to effectively bind to the carbohydrate recognition domain (CRD) of galectin-3. As well as electrostatic and van der Waals interactions, a few strong hydrogen bonds were found to be involved in the binding of bergenin to galectin-3. There is also a plausible π-stacking interaction between the aromatic moiety of bergenin and the His158 residue at the binding site. A 50-ns MD simulation was carried out for the bergenin:galectin-3 complex in a cubic water box with periodic boundary conditions. The MD results showed that the bergenin:galectin-3 complex is highly stable and confirmed the veracity of the docking results, which suggested that bergenin potentially exerts an inhibitory effect on galectin-3. This study therefore sheds new light on the anticancer activity of bergenin and demonstrates that bergenin could potentially be used to develop more potent galectin-3 inhibitors. The study also provides scientific evidence supporting the use of bergenin-containing plants in cancer treatments in Eastern traditional medicine.

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Graphical abstract Bergenin in the galectin-3 binding site

     

An improved method for transformation of Actinidia arguta utilized to demonstrate a central role for MYB110 in regulating anthocyanin accumulation in kiwiberry

Plant Cell, Tissue and Organ Culture (PCTOC) - Drought-tolerant rootstocks have been used to improve production efficiency of graft-propagated crops. Kiwifruit is a high-valued fruit crop of the...     

Foot-and-mouth disease virus VP1 target the MAVS to inhibit type-I interferon signaling and VP1 E83K mutation results in virus attenuation

VP1, a pivotal capsid protein encoded by the foot-and-mouth disease virus (FMDV), plays an important role in receptor-mediated attachment and humoral immune responses. Previous studies show that amino acid changes in the VP1 protein of cell culture-adapted strains of FMDV alter the properties of the virus. In addition, FMDV VP1 modulates host IFN signal transduction. Here, we examined the ability of cell culture-adapted FMDV VP1(83K) and wild-type FMDV VP1(83E) to evade host immunity by blocking mitochondrial antiviral signaling protein (MAVS)/TNF Receptor Associated Factor 3 (TRAF3) mediated cellular innate responses. Wild-type FMDV VP1(83E) interacted specifically with C-terminal TRAF3-binding site within MAVS and this interaction inhibited binding of TRAF3 to MAVS, thereby suppressing interferon-mediated responses. This was not observed for cell culture-adapted FMDV VP1(83K). Finally, chimeric FMDV harboring VP1(83K) showed very low pathogenicity in pigs. Collectively, these data highlight a critical role of VP1 with respect to suppression of type-I IFN pathway and attenuation of FMDV by the E83K mutation in VP1.