A prospective compound screening contest identified broader inhibitors for Sirtuin 1

Potential inhibitors of a target biomolecule, NAD-dependent deacetylase Sirtuin 1, were identified by a contest-based approach, in which participants were asked to propose a prioritized list of 400 compounds from a designated compound library containing 2.5 million compounds using in silico methods and scoring. Our aim was to identify target enzyme inhibitors and to benchmark computer-aided drug discovery methods under the same experimental conditions. Collecting compound lists derived from various methods is advantageous for aggregating compounds with structurally diversified properties compared with the use of a single method. The inhibitory action on Sirtuin 1 of approximately half of the proposed compounds was experimentally accessed. Ultimately, seven structurally diverse compounds were identified

Singlet oxygen induced products of linoleates, 10- and 12-(Z,E)-hydroxyoctadecadienoic acids (HODE), can be potential biomarkers for early detection of type 2 diabetes.

Current diagnostic tests such as glycemic indicators have limitations for early detection of impaired glucose tolerance (IGT), which leads to diabetes. Oxidative stress induced by various oxidants in a random and destructive manner is considered to play an important role in the pathophysiology of a number of human disorders and diseases such as impaired glucose tolerance. We have developed an improved method for the measurement of in vivo lipid peroxidation, where the presence of 8-iso-prostaglandin F2α (8-iso-PGF2α), hydroxyoctadecadienoic acids (HODEs), hydroxyeicosatetraenoic acids (HETEs), and 7-hydroxycholesterol (7-OHCh), as well as their parent molecules, linoleic acid (LA) and cholesterol (Ch), was determined by performing LC-MS/MS (for 8-iso-PGF2α, HODE, and HETE) and GC-MS (for 7-OHCh, LA, and Ch) after reduction with triphenyl phosphine and saponification by potassium hydroxide. We then applied this method to volunteers (n = 57), including normal type (n = 43), "high-normal" (fasting plasma glucose, 100-109 mg/dL, n = 7), pre-diabetic type (IGT, n = 5), and diabetic type (n = 2) subjects who are diagnosed by performing oral glucose tolerance tests (OGTTs). Several biomarkers in plasma, such as insulin, leptin, adiponectin, interleukin-6, tumor necrosis factor-α, high sensitivity-C-reactive protein, HbA1c, and glucose levels were measured during OGTT. We found that the fasting levels of (10- and 12-(Z,E)- HODE)/LA increased significantly with increasing levels of HbA1c and glucose during OGTT and with insulin secretion and resistance index. In conclusion, 10- and 12-(Z,E)-HODE may be prominent biomarkers for the early detection of IGT and "high-normal" type without OGTT

Additional file 1 of Impact of clinical clerkship integrated with clinical ladder on attending physicians’ teaching self-efficacy

Supplementary Material

Typical chromatograms obtained from LC-MS/MS of human plasma samples measured in this study.

<p>(a) Total ion chromatogram, (b) 9-(Z,E)- and (E,E)-HODE, (c) 10- and 12-(Z,E)-HODE, (d) 13-(Z,E)- and (E,E)-HODE, (e) 13-(Z,E)-HODE-d₄, (f) 5-HETE, (g) 12-HETE, (h) 15-HETE, (i) 8–iso-PGF_2α, and (j) 8-iso-PGF_2α-d_4.</p

Correlation between fasting plasma levels of (10- and 12-(Z,E)-HODE)/LA in subjects without diabetic type and the insulinogenic index (A) or Matsuda Index 3 (B) during OGTT.

<p>Correlation between fasting plasma levels of (10- and 12-(Z,E)-HODE)/LA in subjects without diabetic type and the insulinogenic index (A) or Matsuda Index 3 (B) during OGTT.</p

The study design of OGTT performed in this study.

<p>Abbreviations: a, Blood collection; b, Glycometabolism Markers (glucose, insulin, leptin, adiponectin, IL-6, TNF-α); c, Oxidative stress markers (9-(Z,E)-HODE, 9-(E,E)-HODE, 12-(Z,E)-HODE, 10-(Z,E)-HODE, 13-(Z,E)-HODE, 13-(E,E)-HODE, 5HETE, 12HETE, 15HETE, isoPs, linoleic acid, total cholesterol, 7β-hydroxycholesterol).</p

Characteristics of subjects at entry into the oral glucose tolerance test (OGTT).

<p>Data are presented as mean ± standard deviation. One-factor completely randomized design analysis of variance (ANOVA) was used to examine the main effect of subject groups on each index. Significant effects were followed by Tukey's HSD multiple comparisons.</p>*<p>p<0.05,</p>**<p>p<0.01 compared with Group N. a, fasting; b, 60 min after 75 g of oral glucose; c, 120 min after 75 g of oral glucose; d, fasting sugar, 100 -109 mg/dl (defined by the Japan Diabetes Society) Abbreviations : BMI, body mass index; HOMA-IR, homeostasis model assessment of insulin resistance; L/A, Leptin/Adiponectin; hs-CRP, high sensitivity C - reactive protein; ND data not determined.</p

Plasma levels of 10- and 12-(Z,E)-HODE and those divided by linoleic acid (LA) during OGTT.

<p>One-factor repeated measures design analysis of variance (ANOVA) was used to examine the main effect of elapsed time from glucose injection on each index. Significant effects were followed by Tukey's HSD multiple comparisons. a, All subjects; b, Group N; c, Group HN, Group IGT, and Group D.</p