α‑Tocopherol Attenuates the Triglyceride- and Cholesterol-Lowering Effects of Rice Bran Tocotrienol in Rats Fed a Western Diet

Previous studies demonstrated the ability of tocotrienol (T3) to lower levels of lipids, including cholesterol (Cho) and triglycerides (TG). Although α-tocopherol (α-Toc) reportedly inhibits the hypocholesterolemic effect of T3, there is no information about whether α-Toc influences the TG-lowering effect of T3 in vivo. In this study, we investigated the influence of α-Toc on the antihyperlipidemic effects (Cho- and TG-lowering) of rice bran tocotrienols (RBT3) in F344 rats fed a western diet. α-Toc attenuated both the Cho- and TG-lowering effects of RBT3 in vivo, whereas α-Toc alone exhibited no hypolipidemic effects. RBT3-induced <i>Cpt-1a</i> and <i>Cyp7a1</i> gene expression was reduced by α-Toc. Furthermore, coadministration of α-Toc decreased liver and adipose tissue concentrations of tocotrienols in F344 rats. These results indicate that α-Toc has almost no antihyperlipidemic effect in vivo, but abrogates the antihyperlipidemic effect of RBT3 by reducing tissue concentrations of tocotrienols and regulating expression of genes involved in lipid metabolism. Understanding the underlying mechanism of the beneficial effects of T3 on lipid metabolism and the interaction with α-Toc will be important for developing T3-based therapeutics

N₂O flux from the soil treated with different rates of nitrogen and biochar (Experiment 1).

<p>Error bars indicate standard deviation. Arrows indicate the first, second, third and fourth split applications of N fertilizer.</p

Noise annoyance caused by continuous descent approaches compared to regular descent procedures

During Continuous Descent Approaches (CDAs) aircraft glide towards the runway resulting in reduced noise and fuel usage. Here, we investigated whether such landings cause less noise annoyance than a regular stepwise approach. Both landing types were compared in a controlled laboratory setting with a Virtual Community Noise Simulator (VCNS), using four audio samples: an overflight during a regular approach (2000 ft altitude) and three aircraft performing CDAs at respectively 3000, 4000 and 5000 ft. The samples at 2000 ft and 4000 ft were recorded at a countryside road, a 360° photo of which was used for the virtual visuals. The other two CDA samples were derived from the recording at 4000 ft. Participants were asked to rate all flyover samples twice while being immersed in the virtual environment. The CDA at 3000 ft was rated as most annoying, likely due to a longer overflight duration, followed by the regular descent and then the CDAs at 4000 and 5000 ft. As CDAs follow a fairly steady trajectory, it was estimated that they will increase annoyance within an area of approximately 2.5 km2, as compared to regular landings. Outside of this area, CDAs may instead result in less annoyance than regular landings

Soil total N, total C, pH, EC, NH4—N and NO3—N content after 64 days of incubation (Experiment 1).

<p>Data analyzed by two-way ANOVA with the factors of Nitrogen (N) and Biochar (B). Values are mean ± standard variation.</p

Correlation between N₂O emission flux and soil NO3—N concentration on day 8 and 21 of incubation (Experiment 2).

<p>**P<0.01.</p

Soil total N, total C and C/N ratio and C/IN ratio after 60 days of incubation (Experiment 2).

<p>Numbers in the table represent means ± standard deviation. Data analyzed by three-way ANOVA with the factors of Dolomite (D), Biochar (B) and WFPS (%). (D0—No Dolomite, D1—Dolomite, B0—No biochar, RH—Rice husk, SD—Sawdust, BB—Bamboo).</p

N₂O flux from the soil treated with different rates of nitrogen and biochar (Experiment 1).

<p>Error bars indicate standard deviation. Arrows indicate the first, second, third and fourth split applications of N fertilizer.</p

CO₂ flux from the soil treated with different rates of nitrogen and biochar (Experiment 1).

<p>Error bars indicate standard deviation. Arrows indicate the first, second, third and fourth split applications of N fertilizer.</p

Cumulative N₂O and CO₂ emissions after 64 days of incubation.

<p>Data analyzed by two-way ANOVA with the factors of Nitrogen (N) and Biochar (B) (Experiment 1). Values are mean ± standard deviations.</p

Discovery and pharmacological characterization of a new class of prolyl-tRNA synthetase inhibitor for anti-fibrosis therapy

<div><p>Scleroderma has clinical characteristics including skin and other tissue fibrosis, but there is an unmet need for anti-fibrotic therapy. Halofuginone (HF) is a well-known anti-fibrosis agent in preclinical and clinical studies which exerts its effect via inhibition of TGF-β/Smad3 signaling pathway. Recently, prolyl-tRNA synthetase (PRS) was elucidated as a target protein for HF that binds to the proline binding site of the catalytic domain of PRS. Here, we characterized a new class of PRS inhibitor (T-3833261) that is carefully designed in a way that binds to the ATP site of the catalytic domain and does not disrupt binding of proline. The anti-fibrotic activity and the mechanism of action for T-3833261 on TGF-β-induced fibrotic assay were compared with those of HF in primary human skin fibroblast. We evaluated <i>in vivo</i> effect of topical application of T-3833261 and HF on TGF-β-induced fibrotic genes expression in mice. We found that T-3833261 suppressed TGF-β-induced α-smooth muscle actin (α-SMA) and type I collagen α1 (COL1A1) expression through the Smad3 axis in a similar fashion to HF. <i>In vivo</i> topical application of T-3833261 reduced the increase of fibrotic genes expression such as α-Sma, Col1a1 and Col1a2 by TGF-β intradermal injection to the ear of a mouse. We revealed that T-3833261 is more effective than HF under the conditions of high proline concentration, as reported in fibrotic tissues. These results suggest the potential of ATP competitive PRS inhibitors for the treatment of fibrotic diseases such as scleroderma.</p></div