Ｎ末端へミリストイル化を施したCbl-bユビキチン化活性阻害剤は、グルココルチコイド誘導性の筋萎縮を抑制する。

A DGpYMP peptide mimetic of tyrosine608-phosphorylated insulin receptor substrate-1 (IRS-1), named Cblin, was previously shown to significantly inhibit Cbl-b-mediated IRS-1 ubiquitination. In the present study, we developed N-myristoylated Cblin and investigated whether it was effective in preventing glucocorticoid-induced muscle atrophy. Using HEK293 cells overexpressing Cbl-b, IRS-1 and ubiquitin, we showed that the 50% inhibitory concentrations of Cbl-b-mediated IRS-1 ubiquitination by N-myristoylated Cblin and Cblin were 30 and 120 μM, respectively. Regarding the DEX-induced atrophy of C2C12 myotubes, N-myristoylated Cblin was more effective than Cblin for inhibiting the DEX-induced decreases in C2C12 myotube diameter and IRS-1 degradation. The inhibitory efficacy of N-myristoylated Cblin on IRS-1 ubiquitination in C2C12 myotubes was approximately fourfold larger than that of Cblin. Furthermore, N-myristoylation increased the incorporation of Cblin into HEK293 cells approximately 10-folds. Finally, we demonstrated that N-myristoylated Cblin prevented the wet weight loss, IRS-1 degradation, and MAFbx/atrogin-1 and MuRF-1 expression in gastrocnemius muscle of DEX-treated mice approximately fourfold more effectively than Cblin. Taken together, these results suggest that N-myristoylated Cblin prevents DEX-induced skeletal muscle atrophy in vitro and in vivo, and that N-myristoylated Cblin more effectively prevents muscle atrophy than unmodified Cblin

Toxicoproteomic evaluation of carbon nanomaterials in vitro

Carbon nanotubes (CNTs) have already been successfully implemented in various fields, and they are anticipated to have innovative applications in medical science. However, CNTs have asbestos-like properties, such as their nanoscale size and high aspect ratio (> 100). Moreover, CNTs may persist in the body for a long time. These properties are thought to cause malignant mesothelioma and lung cancer. However, based on conventional toxicity assessment systems, the carcinogenicity of asbestos and CNTs is unclear. The reason for late countermeasures against asbestos is that reliable, long-term safety assessments have not yet been developed by toxicologists. Therefore, a new type of long-term safety assessment, different from the existing methods, is needed for carbon nanomaterials. Recently, we applied a proteomic approach to the safety assessment of carbon nanomaterials. In this review, we discuss the basic concept of our approach, the results, the problems, and the possibility of a long-term safety assessment for carbon nanomaterials using the toxicoproteomic approach.ArticleJournal of Proteomics. 74(12):2703-2712 (2011)journal articl

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Effects of Amino Acid, Enzyme Mixture and Phytase Added to Low Protein and Low Phosphorus Diet on Performance and Excretion of Nitrogen and Phosphorus in Broilers.

In the purpose to reducing excretion of nitrogen (N) and phosphorus (P) without the influence of the growth performances and abdominal fat in broilers, a feeding trial and balance test were conducted. Four diets were prepared. The control diets (C) contained 23% crude protein (CP) for 0 to 21 days of age and 19% CP for 22 to 49 days of age, respectively. In the second diets (L), CP were reduced to 19 and 16% for both phases and crystal amino acids were added to be 110% of requirements at both phases. In the third diets (LE), an enzyme mixture (cellulase, xylanase and pectinase) was added to L. In the fourth diets (LEP), non-phytate P were reduced to 0.32% and 0.28% for both phases, and phytase was added. Eight hundred one-day-old broiler chicks, equal number of male and female, were divided into 4 treatments and given free access to one of the diets for 49 days of age, and body weight (BW), feed intake and mortality were recorded. At the end of experiment, 50 chicks per each treatment were slaughtered by bleeding through a jugular vein and eviscerated for the determination of abdominal fat. Using another 10 male broiler chicks per each treatment, excretion of dry matter (DM), N and P were determined by the balance test. There were no significant differences in BW gain, feed intake, feed conversion ratio and mortality among four treatments. Abdominal fat of broilers fed L was significantly heavier than that of other three treatments, and no significant differences were found in abdominal fat among other three treatments. Excretion of DM and N in L, LE and LEP decreased to 91, 84 and 82%, and 73, 70 and 70% of C, respectively. Excretion of P of broilers fed LEP decreased to a half of other three treatments, and there were no differences in P excretion among other three treatments

Effects of Microbial Phytase on Phytate Phosphorus Utilization in Plant Feedstuffs for Broiler Chicks

The reported effects of dietary supplemented microbial phytase on the utilization of phytate phosphorus (pP) differ widely by investigators. In order to clarify the differences, the contents of total phosphorus (P) and pP in commonly used five plant feedstuffs, corn (C), soybean meal (SM), defatted rice bran (RB), wheat bran (WB) and high level flour wheat bran (FWB) were determined, and the effect of microbial phytase on utilization of pP in these feedstuffs was studied using male broiler chicks. The contents of total P in plant feedstuffs were determined to be 0.25, 0.67, 2.81, 1.04 and 0.54%, and those of pP to be 0.15, 0.31, 2.02, 0.71 and 0.32% in C, SM, RB, WB and FWB, respectively. The ratios of pP to total P ranged from 47.2% (for SM) to 71.8% (for RB). The experimental diets were formulated using C, SM, RB, WB or FWB as a sole source of pP. Male broiler chicks were fed the diets supplemented by 0 or 500 phytase units/kg of diet microbial phytase for 10 days from 7 to 17 days of age. There were large differences in pP retention among plant feedstuffs without microbial phytase. Especially the retention was low (5.4%) in the C and high (73.4%) in the WB. The pP retention in SM, RB and FWB were 52.3, 42.5 and 51.1%, respectively. On the other hand, with the addition of microbial phytase, pP retention in C, SM, RB, WB and FWB increased to 69.9, 75.0, 78.6, 86.6 and 84.1%, respectively