Fundamental Toxicological Sciences

2021 - Vol. 8 No. 1

2021 - Vol. 8

Original Article
The influence of long-term ingestion of D-allulose in hypercholesterolemia patients under statin therapy Vol.8, No.1, p.23-31
Misuzu Tanaka , Akane Kanasaki , Noriko Hayashi , Tetsuo Iida , Koji Murao
Released: April 22, 2021
Abstract Full Text PDF[833K]

D-allulose is a non-caloric natural sugar with health benefits. A few clinical trials with continuous D-allulose intake have been reported; one indicated significant increase in low-density lipoprotein cholesterol (LDL-C) levels, though the study was not a randomized controlled trial. D-allulose is predicted to be widely used in the near future by various people; therefore, the influence of D-allulose on those who have high risk for LDL-C elevation needs to be determined. Here, the effects of D-allulose on LDL-C levels in patients with hypercholesterolemia under statin therapy were investigated in a randomized controlled trial. Twenty subjects were randomly assigned to two groups: 15 g D-allulose/day or 15 g erythritol/day (placebo); each subject consumed a daily test substance for 48 weeks. Clinical examinations were performed every eight weeks, from initial consumption until week 52. No significant increase in LDL-C was observed, although significant decrease was observed in high-density lipoprotein cholesterol (HDL-C) in the D-allulose group. HDL-C values stayed within the standard ranges during the consumption period, and the mechanism was reported to be anti-atherosclerotic. In terms of risk assessment, D-allulose did not affect all risk factors that were measured for atherosclerotic cardiovascular disease. Taken together, these results suggested that long-term D-allulose consumption did not affect LDL-C values and atherosclerotic cardiovascular disease risk in patients with hypercholesterolemia under statin therapy.

Letter
Ouabagenin, an aglycone of cardiotonic steroid ouabain, functions as LXR ligand but avoids the increase in the SREBP-1 by inducing Kr├╝ppel-like factor 15 Vol.8, No.1, p.17-22
Tomofumi Fujino , Kouta Sugizaki , Saki Ohkawa , Sana Fujikawa , Toshiyuki Oshima , Makio Hayakawa
Released: March 27, 2021
Abstract Full Text PDF[1M]

Liver X receptor (LXR)-alpha and LXR-beta are nuclear receptors activated by oxysterols. They exhibit differential expression patterns and may perform different functional roles. Here we show that LXR-alpha and LXR-beta mutually regulate the expression levels of their counter parts in the normal hepatocyte-derived cell line Fa2N-4. In addition, we demonstrate that ouabagenin (OBG), which was identified as a naturally occurring LXR ligand without causing hepatic steatosis, dramatically increases the expression of LXR-alpha in Fa2N-4 cells that overexpress LXR-beta. However, the expression level of sterol response element binding protein 1c (SREBP-1c), a known target of LXR-alpha, remains marginal in OBG-treated Fa2N-4 cells, in which LXR-alpha expression is upregulated by LXR-beta. Furthermore, we show that OBG stimulates the expression of Krüppel-like factor 15 (KLF15) that is known to form a repressive complex with LXR/RXR and corepressor RIP140, thereby reducing SREBP-1c expression. Thus, we propose a novel mechanism that OBG avoids the increase in the expression of SREBP-1c through the upregulation of KLF15.

Original Article
Genotoxicity of Monascus Color Y-001 Vol.8, No.1, p.7-16
Ryosuke Sato , Michihito Takabe , Takahiro Ishii , Norio Imai , Yuko Doi , Toyohiko Aoki
Released: March 09, 2021
Abstract Full Text PDF[747K]

The genotoxic potential of Monascus Color Y-001 was assessed using the standard battery of assays including the in vitro reverse mutation test in bacteria (Ames test), the in vitro chromosomal aberration test in mammalian cells and the in vivo micronucleus test in rats. The results of the Ames test, the chromosomal aberration test in CHL/IU cells with and without S9 mix (metabolic activation) and the in vivo bone marrow micronucleus test in rats were all negative. Therefore, it is concluded that Monascus Color Y-001 does not possess any genotoxic risk in humans.

Toxicomics Report
Comprehensive analysis of the alteration of plasma miRNA expression level in mice exposed to diesel exhaust Vol.8, No.1, p.1-6
Ken Tachibana , Iori Kodaira , Noriko Kuroiwa , Ryo Uzuki , Yusuke Shinkai , Ken Takeda
Released: February 12, 2021
Abstract Full Text PDF[768K]

MicroRNAs (miRNAs) are small non-coding RNAs of ~22 nucleotides in length that play important roles in controlling a huge range of eukaryotic cell functions. Many studies have shown that abnormal expression levels of miRNAs are associated with many diseases and detrimental health effects caused by exposure to environmental pollutants and particulate matter. As a number of reports suggest that profiles of miRNAs in body fluids reflect physiological and pathological status, extracellular miRNAs, especially in plasma and serum, are being focused on as candidate disease biomarkers. Although these phenomena suggest that expression levels of plasma miRNAs can also be used as biomarkers for the detection of adverse health effects caused by exposure to environmental pollutants, there are still few studies on this subject. In the present study, we used diesel exhaust (DE) and filtered-DE (F-DE), which is DE with the particulate matter removed, as a model for environmental pollutant exposure and comprehensively analyzed alteration of the expression levels of plasma miRNAs in mice using a LNA miRNA microarray. MiRNA microarray analyses showed altered expression level of 5 plasma miRNAs (miR-1983, miR-720, miR-1957, miR-335-3p, and miR-1897-5p) in the DE-exposed group and F-DE-exposed group. The results show both the possibility that exposure to various environmental chemicals including DE alters plasma miRNAs and the potential for plasma miRNAs to be used as biomarkers of exposure to these chemicals.