A Daphnane Diterpenoid Isolated from Wikstroemia polyantha Induces an Inflammatory Response and Modulates miRNA Activity

MicroRNAs (miRNAs) are endogenously expressed single-stranded ∼21–23 nucleotide RNAs that inhibit gene expression post-transcriptionally by binding imperfectly to elements usually within the 3′untranslated region (3′UTR) of mRNAs. Small interfering RNAs (siRNAs) mediate site-specific cleavage by binding with perfect complementarity to RNA. Here, a cell-based miRNA reporter system was developed to screen for compounds from marine and plant extracts that inhibit miRNA or siRNA activity. The daphnane diterpenoid genkwanine M (GENK) isolated from the plant Wikstroemia polyantha induces an early inflammatory response and can moderately inhibit miR-122 activity in the liver Huh-7 cell line. GENK does not alter miR-122 levels nor does it directly inhibit siRNA activity in an in vitro cleavage assay. Finally, we demonstrate that GENK can inhibit HCV infection in Huh-7 cells. In summary, the development of the cell-based miRNA sensor system should prove useful in identifying compounds that affect miRNA/siRNA activity

Structure sensitivity of the oxygen evolution reaction catalyzed by cobalt (II,III) oxide

Quantum chemical calculations and simulated kinetics were used to examine the structure sensitivity of the oxygen evolution reaction on several surface terminations of Co3O4. Active sites were identified on both the (001) and (311) surfaces consisting of two adjacent Co(IV) cations connected by bridging oxos. Formation of the O-O bond proceeds on these sites by nucleophilic attack of water on a bridging oxo. It was found that the relative turnover frequencies for the different sites are highly dependent on the overpotential, with the dual-Co site on the (311) surface being most active at medium overpotentials where O-O bond formation by water addition is rate limiting. A similar dual-Co site on the (001) surface is most active at low overpotentials where O2 release is rate limiting, and a single-Co site on the (110) surface is most active at overpotentials that are high enough (>0.8 V) to form a significant concentration of highly reactive terminal Co(V)=O species. Two overpotential-dependent Sabatier relationships were identified based on the Brønsted basicity and redox potential of the active site, explaining the change in the active site with overpotential. The (311) dual-Co site that is most active at medium overpotentials is consistent with recent experimental observations suggesting that a defect site is responsible for the observed oxygen evolution activity and that a modest concentration of superoxo intermediates is present on the surface. Importantly, we find that it is essential to consider the kinetics of the water addition and O2 release steps rather than only the thermodynamics

Quantum 1 chemistry of the oxygen evolution reaction on cobalt(II,III) oxide:implications for designing the optimal catalyst

Density functional theory is used to examine the changes in electronic structure that occur during the oxygen evolution reaction (OER) catalyzed by active sites on three different surface terminations of Co3O4. These three active sites have reactive oxo species with differing degrees of coordination by Co cations – a µ3-oxo on the (311) surface, a µ2-oxo on the (110)-A surface, and an η-oxo on the (110)-B surface. The kinetically relevant step on all surfaces over a wide range of applied potentials is the nucleophilic addition of water to the oxo, which is responsible for formation of the O–O bond. The intrinsic reactivity of a site for this step is found to increase as the coordination of the oxo decreases with the µ3-oxo on the (311) surface being the least reactive and the η-oxo on the (110)-B surface being the most reactive. A detailed analysis of the electronic changes occurring during water addition on the three sites reveals that this trend is due to both a decrease in the attractive local Madelung potential on the oxo and a decrease in electron withdrawal from the oxo by Co neighbors. Applying a similar electronic structure analysis to the oxidation steps preceding water addition in the catalytic cycle shows that analogous electronic changes occur during this process, explaining a correlation observed between the oxidation potential of a site and its intrinsic reactivity for water addition. This concept is then used to specify criteria for the design of an optimal OER catalyst at a given applied potential.\u3cbr/\u3e\u3cbr/\u3

Pathways to Interleukin-6 in Healthy Males and Serious Leisure Male Athletes: Physical Activity, Body Composition and Age

Physical activity (PA) is beneficial to overall health, in part due to physiological changes that lower risk factors for cardiovascular disease, including reduced inflammation. However, the mechanism by which PA reduces inflammation is unclear. One possible pathway is that PA improves body composition which in turn reduces inflammation. To test this hypothesis, we used structural equation modeling (SEM) to assess PA-body composition –inflammation pathways, as well as influences of age. In a sample of 72 healthy males with a range of PA profiles (age 18–65, mean ±sd  =  ), we measured PA as metabolic equivalent tasks (as per the International PA Questionnaire), body composition as percent body fat, lean mass, and fat mass, and inflammation as plasma interleukin-6 (IL-6). We treated body composition in the SEM analysis as a latent variable indicated by the three measures. We performed statistical corrections for missing values and one outlier. The model demonstrated significant effects of PA on IL-6 both directly and through body composition. Percent body fat, fat mass, and lean mass were significant indicators of the body composition latent variable. Additionally, age showed an indirect effect on IL-6 through body composition, but no direct effect. The findings suggest that PA does improve inflammatory profile through improving body composition, but that other pathways also exist

Intracellular nicotinamide adenine dinucleotide promotes TNF-induced necroptosis in a sirtuin-dependent manner.

Cellular necrosis has long been regarded as an incidental and uncontrolled form of cell death. However, a regulated form of cell death termed necroptosis has been identified recently. Necroptosis can be induced by extracellular cytokines, pathogens and several pharmacological compounds, which share the property of triggering the formation of a RIPK3-containing molecular complex supporting cell death. Of interest, most ligands known to induce necroptosis (including notably TNF and FASL) can also promote apoptosis, and the mechanisms regulating the decision of cells to commit to one form of cell death or the other are still poorly defined. We demonstrate herein that intracellular nicotinamide adenine dinucleotide (NAD(+)) has an important role in supporting cell progression to necroptosis. Using a panel of pharmacological and genetic approaches, we show that intracellular NAD(+) promotes necroptosis of the L929 cell line in response to TNF. Use of a pan-sirtuin inhibitor and shRNA-mediated protein knockdown led us to uncover a role for the NAD(+)-dependent family of sirtuins, and in particular for SIRT2 and SIRT5, in the regulation of the necroptotic cell death program. Thus, and in contrast to a generally held view, intracellular NAD(+) does not represent a universal pro-survival factor, but rather acts as a key metabolite regulating the choice of cell demise in response to both intrinsic and extrinsic factors.Cell Death and Differentiation advance online publication, 22 May 2015; doi:10.1038/cdd.2015.60.SCOPUS: ar.jinfo:eu-repo/semantics/publishe