The Effects of Pharmacological Inhibition of Histone Deacetylase 3 (HDAC3) in Huntingtons Disease Mice.

An important epigenetic modification in Huntingtons disease (HD) research is histone acetylation, which is regulated by histone acetyltransferase and histone deacetylase (HDAC) enzymes. HDAC inhibitors have proven effective in HD model systems, and recent work is now focused on functional dissection of the individual HDAC enzymes in these effects. Histone deacetylase 3 (HDAC3), a member of the class I subfamily of HDACs, has previously been implicated in neuronal toxicity and huntingtin-induced cell death. Hence, we tested the effects of RGFP966 ((E)-N-(2-amino-4-fluorophenyl)-3-(1-cinnamyl-1H-pyrazol-4-yl)acrylamide), a benzamide-type HDAC inhibitor that selectively targets HDAC3, in the N171-82Q transgenic mouse model of HD. We found that RGFP966 at doses of 10 and 25 mg/kg improves motor deficits on rotarod and in open field exploration, accompanied by neuroprotective effects on striatal volume. In light of previous studies implicating HDAC3 in immune function, we measured gene expression changes for 84 immune-related genes elicited by RGFP966 using quantitative PCR arrays. RGFP966 treatment did not cause widespread changes in cytokine/chemokine gene expression patterns, but did significantly alter the striatal expression of macrophage migration inhibitory factor (Mif), a hormone immune modulator associated with glial cell activation, in N171-82Q transgenic mice, but not WT mice. Accordingly, RGFP966-treated mice showed decreased glial fibrillary acidic protein (GFAP) immunoreactivity, a marker of astrocyte activation, in the striatum of N171-82Q transgenic mice compared to vehicle-treated mice. These findings suggest that the beneficial actions of HDAC3 inhibition could be related, in part, with lowered Mif levels and its associated downstream effects

Temperature response of soil respiration in a Chinese pine plantation: hysteresis and seasonal vs. diel Q10.

Although the temperature response of soil respiration (Rs ) has been studied extensively, several issues remain unresolved, including hysteresis in the Rs -temperature relationship and differences in the long- vs. short-term Rs sensitivity to temperature. Progress on these issues will contribute to reduced uncertainties in carbon cycle modeling. We monitored soil CO2 efflux with an automated chamber system in a Pinus tabulaeformis plantation near Beijing throughout 2011. Soil temperature at 10-cm depth (Ts ) exerted a strong control over Rs , with the annual temperature sensitivity (Q10) and basal rate at 10°C (Rs10) being 2.76 and 1.40 µmol m(-2) s(-1), respectively. Both Rs and short-term (i.e., daily) estimates of Rs10 showed pronounced seasonal hysteresis with respect to Ts , with the efflux in the second half of the year being larger than that early in the season for a given temperature. The hysteresis may be associated with the confounding effects of microbial population dynamics and/or litter input. As a result, all of the applied regression models failed to yield unbiased estimates of Rs over the entire annual cycle. Lags between Rs and Ts were observed at the diel scale in the early and late growing season, but not in summer. The seasonality in these lags may be due to the use of a single Ts measurement depth, which failed to represent seasonal changes in the depth of CO2 production. Daily estimates of Q10 averaged 2.04, smaller than the value obtained from the seasonal relationship. In addition, daily Q10 decreased with increasing Ts , which may contribute feedback to the climate system under global warming scenarios. The use of a fixed, universal Q10 is considered adequate when modeling annual carbon budgets across large spatial extents. In contrast, a seasonally-varying, environmentally-controlled Q10 should be used when short-term accuracy is required

Extreme rainfall impacts on soil CO2 efflux in an urban forest ecosystem in Beijing, China

Extreme rainfall events are infrequent disturbances that affect urban environments and soil respiration (Rs). Using data measured in an urban forest ecosystem in Beijing, China, we examined the link between gross primary production (GPP) and soil respiration on a diurnal scale during an extreme rainfall event (i.e., the ‘21 July 2012 event’), and examined diel and seasonal environmental controls on Rs. Over the seasonal cycle, Rs increased exponentially with soil temperature (Ts). In addition, Rs was hyperbolically related to soil volumetric water content (VWC), increasing with VWC below a threshold of 0.17 m3 m-3, and then decreasing with further increases in VWC. Following the extreme rainfall event (177 mm), Rs showed an abrupt decrease and then maintained a low value of ~0.3 μmol m-2 s-1 for about 8 h as soil VWC reached the field capacity (0.34 m3 m-3). Rs became decoupled from Ts and increased very slowly, while GPP showed a greater increase. A bivariate Q10-hyperbolical model, which incorporates both Ts and VWC effects, better fit Rs than the Q10 model in summer, but not for whole year.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Lipoamide Acts as an Indirect Antioxidant by Simultaneously Stimulating Mitochondrial Biogenesis and Phase II Antioxidant Enzyme Systems in ARPE-19 Cells

<div><p>In our previous study, we found that pretreatment with lipoamide (LM) more effectively than alpha-lipoic acid (LA) protected retinal pigment epithelial (RPE) cells from the acrolein-induced damage. However, the reasons and mechanisms for the greater effect of LM than LA are unclear. We hypothesize that LM, rather than the more direct antioxidant LA, may act more as an indirect antioxidant. In the present study, we treated ARPE-19 cells with LA and LM and compared their effects on activation of mitochondrial biogenesis and induction of phase II enzyme systems. It is found that LM is more effective than LA on increasing mitochondrial biogenesis and inducing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation to the nucleus, leading to an increase in expression or activity of phase II antioxidant enzymes (NQO-1, GST, GCL, catalase and Cu/Zn SOD). Further study demonstrated that mitochondrial biogenesis and phase II enzyme induction are closely coupled via energy requirements. These results suggest that LM, compared with the direct antioxidant LA, plays its protective effect on oxidative damage more as an indirect antioxidant to simultaneously stimulate mitochondrial biogenesis and induction of phase II antioxidant enzymes.</p></div

The effects of LM on oxygen consumption (A), mitochondrial membrane potential (MMP) (B), ROS production (C); cellular ATP level (D) and the expression of MnSOD,Trx2,Prx3,and Prx5 (E).

<p>ARPE-19 cells were treated with 40 μmol/L LM for 48 hours; then the following assays were carried out immediately. <b>(A)</b> LM promoted oxygen consumption. Results are expressed as the rate of oxygen consumption, with media without cells used as a blank. Values are means ± SEM from three independent experiments; three parallel measurements were used for each sample in every experiment. <b>(B)</b> LM treatment increased MMP as determined by JC-1 staining. Values are means ± SEM of the ratio of fluorescence at 590 nm to 530 nm from three independent experiments; 4 parallel wells for each group were used in each experiment. <b>(C)</b> LM treatment decreased ROS production examined by DCF-DA staining. Values are means ± SEM of 8 parallel wells of a representative experiment, from four independent experiments each showing similar trends. (D) LM treatment decreased cellular ATP level. Values are means ± SEM from 3 independent experiments. (E) Expression of MnSOD,Trx2,Prx3,and Prx5. ARPE-19 cells were treated with 40 μmol/L LM or LA for 48 h; then RNA was isolated and reverse-transcribed to cDNA. Real time PCR was employed to measure expression levels of the indicated genes. The results (from 5 independent experiments) are expression ratios of the target genes to 18SrRNA, and are normalized to control (control = 100). C stands for control, LM stands for 40 μmol/L LM treatment and LA stands for 40 μmol/L LA treatment. Statistical significance was established by one way ANOVA followed by the Tukey test (A, B, C, D) or LSD test (E). * p<0.05, ** p<0.01 vs. untreated control (0 μmol/L); ^#p<0.05, ^## p<0.01 vs. LA.</p