著者

Tomoka Hisaki Maki Aiba née Kaneko Morihiko Hirota Masato Matsuoka Hirokazu Kouzuki

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.2, pp.95-108, 2020 (Released:2020-02-15)

参考文献数

48

被引用文献数

8

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We present a systematic, comprehensive and reproducible weight-of-evidence approach for predicting the no-observed-adverse-effect level (NOAEL) for systemic toxicity by using read-across and quantitative structure-activity relationship (QSAR) models to fill gaps in rat repeated-dose and developmental toxicity data. As a case study, we chose valproic acid, a developmental toxicant in humans and animals. High-quality in vivo oral rat repeated-dose and developmental toxicity data were available for five and nine analogues, respectively, and showed qualitative consistency, especially for developmental toxicity. Similarity between the target and analogues is readily defined computationally, and data uncertainties associated with the similarities in structural, physico-chemical and toxicological properties, including toxicophores, were low. Uncertainty associated with metabolic similarity is low-to-moderate, largely because the approach was limited to in silico prediction to enable systematic and objective data collection. Uncertainty associated with completeness of read-across was reduced by including in vitro and in silico metabolic data and expanding the experimental animal database. Taking the “worst-case” approach, the smallest NOAEL values among the analogs (i.e., 200 and 100 mg/kg/day for repeated-dose and developmental toxicity, respectively) were read-across to valproic acid. Our previous QSAR models predict repeated-dose NOAEL of 148 (males) and 228 (females) mg/kg/day, and developmental toxicity NOAEL of 390 mg/kg/day for valproic acid. Based on read-across and QSAR, the conservatively predicted NOAEL is 148 mg/kg/day for repeated-dose toxicity, and 100 mg/kg/day for developmental toxicity. Experimental values are 341 mg/kg/day and 100 mg/kg/day, respectively. The present approach appears promising for quantitative and qualitative in silico systemic toxicity prediction of untested chemicals.

著者

Yuto Amano Hiroshi Honda Ryusuke Sawada Yuko Nukada Masayuki Yamane Naohiro Ikeda Osamu Morita Yoshihiro Yamanishi

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.3, pp.137-149, 2020 (Released:2020-03-06)

参考文献数

47

被引用文献数

5

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In silico models for predicting chemical-induced side effects have become increasingly important for the development of pharmaceuticals and functional food products. However, existing predictive models have difficulty in estimating the mechanisms of side effects in terms of molecular targets or they do not cover the wide range of pharmacological targets. In the present study, we constructed novel in silico models to predict chemical-induced side effects and estimate the underlying mechanisms with high general versatility by integrating the comprehensive prediction of potential chemical-protein interactions (CPIs) with machine learning. First, the potential CPIs were comprehensively estimated by chemometrics based on the known CPI data (1,179,848 interactions involving 3,905 proteins and 824,143 chemicals). Second, the predictive models for 61 side effects in the cardiovascular system (CVS), gastrointestinal system (GIS), and central nervous system (CNS) were constructed by sparsity-induced classifiers based on the known and potential CPI data. The cross validation experiments showed that the proposed CPI-based models had a higher or comparable performance than the traditional chemical structure-based models. Moreover, our enrichment analysis indicated that the highly weighted proteins derived from predictive models could be involved in the corresponding functions of the side effects. For example, in CVS, the carcinogenesis-related pathways (e.g., prostate cancer, PI3K-Akt signal pathway), which were recently reported to be involved in cardiovascular side effects, were enriched. Therefore, our predictive models are biologically valid and would be useful for predicting side effects and novel potential underlying mechanisms of chemical-induced side effects.

著者

Mei Tsuchida Takumi Yokosawa Takuya Noguchi Tatsuya Shimada Mayuka Yamada Yuto Sekiguchi Yusuke Hirata Atsushi Matsuzawa

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.45, no.4, pp.219-226, 2020 (Released:2020-04-01)

参考文献数

47

被引用文献数

2 16

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Tumor necrosis factor receptor-associated factor 2 (TRAF2) is an essential component of tumor necrosis factor-α (TNF-α) signaling that regulates nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, and compelling evidence has demonstrated that TRAF2 suppresses TNF-α-induced cytotoxicity. On the other hand, it has been reported that oxidative stress-induced cytotoxicity is potentiated by TRAF2, indicating that TRAF2 both positively and negatively regulates stress-induced cytotoxicity in a context-specific manner. However, the causal role of TRAF2 in DNA damage response (DDR) remains to be explored. In this study, we assessed the function of TRAF2 in DDR induced by cisplatin, a representative DNA-damaging agent, and found that TRAF2 exerts pro-apoptotic activity through p53-dependent mechanisms at least in human fibrosarcoma cell line HT1080. TRAF2 deficient cells exhibit significant resistance to cell death induced by cisplatin, accompanied by the reduction of both p53 protein level and caspase-3 activation. Moreover, cisplatin-induced JNK activation was attenuated in TRAF2-deficient cells, and pharmacological inhibition of JNK signaling suppressed p53 stabilization. These results suggest that TRAF2 promotes p53-dependent apoptosis by activating the JNK signaling cascade in HT1080 cells. Thus, our data demonstrate a novel function of TRAF2 in cisplatin-induced DDR as a pro-apoptotic protein.

著者

Yuto Sekiguchi Mayuka Yamada Takuya Noguchi Chise Noomote Mei Tsuchida Yuki Kudoh Yusuke Hirata Atsushi Matsuzawa

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.44, no.6, pp.435-440, 2019 (Released:2019-06-04)

参考文献数

24

被引用文献数

3 15

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Fas/CD95 plays a pivotal role in T cell-mediated cytotoxicity. Accumulating evidence has suggested that resistance to Fas-mediated apoptosis contributes to the escape of cancer cells from immune destruction, and allows to undergo proliferation and outgrowth of cancer cells. In this study, we found that the anti-cancer drug gefitinib, a tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), has an ability to enhance Fas-mediated cytotoxicity. In the presence of nontoxic concentrations of gefitinib, Fas-induced activation of caspase-8 and subsequent apoptosis was dramatically promoted, suggesting that gefitinib increases the sensitivity to Fas-mediated apoptosis. Interestingly, the effects of gefitinib were observed in EGFR or p53 knockout (KO) cells. These observations indicate that both EGFR and p53 are dispensable for the enhancement. On the other hand, gefitinib clearly downregulated heat shock protein 70 (HSP70) as previously reported. Considering that HSP70 contributes to protection of cells against Fas-mediated apoptosis, gefitinib may increase the sensitivity to Fas-mediated apoptosis by downregulating HSP70. Thus, our findings reveal novel properties of gefitinib, which may provide insight into the alternative therapeutic approaches of gefitinib for Fas-resistant tumors.

著者

Jin Hee Kim

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.44, no.4, pp.237-244, 2019 (Released:2019-04-03)

参考文献数

43

被引用文献数

2 23

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Di(2-ethylhexyl) phthalate (DEHP) is widely used in polyvinylchloride-based materials and remains intact in the environment. Lungs are one route of entry of DEHP into the body; however, there is limited information on the effects and mechanism of action of DEHP on non-small cell lung cancer (NSCLC). Here, we addressed this by examining the effect of DEHP on the proliferation of A549 human lung adenocarcinoma cells by MTS assay. The induction of inflammation and epithelial-to-mesenchymal transition (EMT), as well as activation of the mitogen-activated protein kinase (MAPK) and Wnt/β-catenin signaling pathways, were assessed by western blot and real-time polymerase chain reaction. Although there were discrepancies in the concentration, DEHP treatment enhanced A549 cell viability accompanied by increased mRNA and protein levels of inflammation-related factors, such as matrix metalloproteinase-9 and nuclear factor-κB. Additionally, EMT was activated in cells according to decreased E-cadherin and increased vimentin expression. Furthermore, MAPK pathway components, including phosphorylated p38 and c-Jun N-terminal kinase, and Wnt/β-catenin pathway components, including phosphorylated glycogen synthase kinase 3β and β-catenin, as well as their downstream genes c-Myc and cyclin D1, were upregulated in the presence of DEHP. These results suggest that DEHP promotes NSCLC progression by promoting cell proliferation, inflammation, and EMT via activation of Wnt/β-catenin signaling.

著者

Masakazu Umezawa Hitoshi Tainaka Natsuko Kawashima Midori Shimizu Ken Takeda

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.37, no.6, pp.1247-1252, 2012-12-01 (Released:2012-12-01)

参考文献数

25

被引用文献数

34 40

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The production of man-made nanoparticles is increasing in nanotechnology, and health effect of nanomaterials is of concern. We previously reported that fetal exposure to titanium dioxide (TiO2) affects the brain of offspring during the perinatal period. The aim of this study was to extract candidate brain regions of interest using a specific group of Medical Subject Headings (MeSH) from a microarray dataset of the whole brain of mice prenatally exposed to TiO2 nanoparticle. After subcutaneous injection of TiO2 (total 0.4 mg) into pregnant mice on gestational days 6-15, brain tissues were collected from male fetuses on embryonic day 16 and from male pups on postnatal days 2, 7, 14 and 21. Gene expression changes were determined by microarray and analyzed with MeSH indicating brain regions. As a result, a total of twenty-one MeSH were significantly enriched from gene expression data. The results provide data to support the hypothesis that prenatal TiO2 exposure results in alteration to the cerebral cortex, olfactory bulb and some regions intimately related to dopamine systems of offspring mice. The genes associated with the striatum were differentially expressed during the perinatal period, and those associated with the regions related to dopamine neuron system and the prefrontal region were dysregulated in the later infantile period. The anatomical information gave us clues as to the mechanisms that underlie alteration of cerebral gene expression and phenotypes induced by fetal TiO2 exposure.

著者

Yusuke Aratsu Reo Odagiri Rie Shoji Kouki Watanabe Takeshi Kumagai Sawako Shindo Takamitsu Sasaki Kiyoshi Nagata

出版者

The Japanese Society of Toxicology

雑誌

Fundamental Toxicological Sciences (ISSN:2189115X)

巻号頁・発行日

vol.4, no.5, pp.229-239, 2017-10-05 (Released:2017-10-05)

参考文献数

27

被引用文献数

1 1

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CYP3A4 is an important drug-metabolizing enzyme induced by various compounds causing drug-drug interactions. However, the molecular mechanism of CYP3A4 induction is not completely understood. CYP3A4 induction is caused by pregnane X receptor (PXR) through binding to some PXR binding elements. These elements comprise an everted repeat separated by six nucleotides in the promoter region and distal nuclear receptor binding element 1 (dNR-1) as well as the essential distal nuclear receptor binding element for CYP3A4 induction (eNR3A4) in the enhancer region of the CYP3A4 gene. Recently, we found that polycyclic aromatic hydrocarbons including anthracene induce CYP3A4 in HepG2 cells with a different induction profile from that of rifampicin (RF), a typical PXR ligand. When a CYP3A4 reporter plasmid in which the eNR3A4 DNA fragment binds directly to the CYP3A4 promoter (-362 bases) was evaluated in a reporter assay, dibenz[a,h]anthracene (DBA) induced reporter activity, while RF did not. To be induced reporter activity by RF, more 14 nucleotides 5′ upstream of the eNR3A4 (rifampicin eNR3A4: reNR3A4) DNA fragment were required. However, eNR3A4 and reNR3A4 did not respond to recombinant PXR without dNR-1. These results suggest that eNR3A4 and reNR3A4 are necessary for CYP3A4 induction by DBA and RF, respectively, and that dNR-1 is indispensable for full induction through PXR.

著者

Eisuke Kume Yuya Okayama Mituru Sugiyama Hiroyuki Takahashi Tomoko Muto Michael F. Wempe Hiroshi Ikegami Shin Wakui

出版者

The Japanese Society of Toxicology

雑誌

Fundamental Toxicological Sciences (ISSN:2189115X)

巻号頁・発行日

vol.10, no.3, pp.R1, 2023 (Released:2023-06-06)

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Editor’s Announcement Quantitative morphometric analysis of vimentin filaments in Sertoli cells of rats after in utero DBP exposureEisuke Kume, Yuya Okayama, Mituru Sugiyama, Hiroyuki Takahashi, Tomoko Muto, Michael F. Wempe, Hiroshi Ikegami, Shin Wakui(Fundamental Toxicological Sciences, 4, 85-93, 2017) I have retracted the above paper as Editor-in-Chief of Fundamental Toxicological Sciences since I have serious concerns about it, primarily due to inappropriate authorship on a non-negligible scale.Since the possibility of inappropriate authorship in this paper was raised, I contacted the co-authors to confirm this point. I found out that several of them considered their listing as co-authors to be inappropriate. In addition, more than half of the co-authors agreed to the retraction of this paper.These facts raise concerns about the paper. From the standpoint of maintaining the integrity of the research community, I felt that such a paper should be retracted at once.Accordingly, I sent a summary of my concerns about this paper to the corresponding author, Dr. Shin Wakui. I also had an online interview with him to discuss this matter. I told Dr. Wakui that inappropriate authorship on a non-negligible scale is a serious problem that raises concerns about the paper.I prepared a draft of this Editor’s Announcement and sent it to Dr. Wakui for review prior to revision and release. Although he did not agree to the retraction, I have decided to take this action from the standpoint of maintaining the integrity of the research community.I coordinated my response to this issue with Dr. Toshiyuki Kaji, Editor-in-Chief of The Journal of Toxicological Sciences, a sister journal of Fundamental Toxicological Sciences.Akira Naganuma, Ph.D.Editor-in-ChiefFundamental Toxicological Sciences

著者

Eisuke Kume Yuya Okayama Mituru Sugiyama Hiroyuki Takahashi Tomoko Muto Michael F. Wempe Hiroshi Ikegami Shin Wakui

出版者

The Japanese Society of Toxicology

雑誌

Fundamental Toxicological Sciences (ISSN:2189115X)

巻号頁・発行日

vol.4, no.2, pp.85-93, 2017-05-13 (Released:2017-05-13)

参考文献数

18

被引用文献数

1 1

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This article was retracted. See the Notification.

著者

Masaya Motohashi Michael F. Wempe Tomoko Mutou Yuya Okayama Norio Kansaku Hiroyuki Takahashi Masahiro Ikegami Masao Asari Shin Wakui

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.48, no.6, pp.R1, 2023 (Released:2023-06-06)

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Editor’s AnnouncementIn utero-exposed di(n-butyl) phthalate induce dose dependent, age-related changes of morphology and testosterone-biosynthesis enzymes/associated proteins of Leydig cell mitochondria in ratsMasaya Motohashi, Michael F. Wempe, Tomoko Mutou, Yuya Okayama, Norio Kansaku, Hiroyuki Takahashi, Masahiro Ikegami, Masao Asari, Shin Wakui(The Journal of Toxicological Sciences, 41, 195-206, 2016) I have retracted the above paper as Editor-in-Chief of The Journal of Toxicological Sciences since I have serious concerns about it, primarily due to inappropriate authorship on a non-negligible scale.When it was brought to my attention that there was inappropriate authorship in this paper, I contacted the co-authors to confirm this point. I found out that the majority of them considered their listing as co-authors to be inappropriate. In addition, the majority agreed to the retraction of this paper.These facts raise concerns about the paper. From the standpoint of maintaining the integrity of the research community, I felt that such a paper should be retracted at once.Accordingly, I sent a summary of my concerns about the paper to the corresponding author, Dr. Shin Wakui. I also had an online interview with him to discuss this matter. I told Dr. Wakui that inappropriate authorship on a non-negligible scale is a serious problem that raises concerns about the paper.I prepared a draft of this Editor’s Announcement and sent it to Dr. Wakui for review prior to revision and release. Although he did not agree to the retraction, I have decided to take this action from the standpoint of maintaining the integrity of the research community.I coordinated my response to this issue with Dr. Akira Naganuma, Editor-in-Chief of Fundamental Toxicological Sciences, a sister journal of The Journal of Toxicological Sciences. Toshiyuki Kaji, Ph.D.Editor-in-ChiefThe Journal of Toxicological Sciences

著者

Masaya Motohashi Michael F. Wempe Tomoko Mutou Yuya Okayama Norio Kansaku Hiroyuki Takahashi Masahiro Ikegami Masao Asari Shin Wakui

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.41, no.2, pp.195-206, 2016-04-01 (Released:2016-03-10)

参考文献数

36

被引用文献数

14 16

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This article was retracted. See the Notification.

著者

Berenyce González-Marín María Elena Calderón-Segura Ana Karen González Pérez Luis Gerardo Moreno Ciénega

出版者

The Japanese Society of Toxicology

雑誌

Fundamental Toxicological Sciences (ISSN:2189115X)

巻号頁・発行日

vol.8, no.3, pp.81-88, 2021 (Released:2021-07-27)

参考文献数

43

被引用文献数

1

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Movento® 240SC and Envidor® 240SC are new insecticide derivatives of tetramic acid belonging to a keto-enol pesticide family. However, few studies have reported genotoxic effects in nontarget organisms. In the present study, the genotoxic effects of Movento® 240SC and Envidor® 240SC on Drosophila melanogaster ovaries were analyzed using the alkaline comet assay. Simultaneously, we determined the LD50 for both insecticides. Virgin females were exposed to food at three sublethal concentrations (11.2, 22.4, 37.3 mg/L) of Movento® 240SC and (12.3, 24.6, 41.1 mg/L) of Envidor® 240SC for 72 hr. As a negative control group, females were exposed to food without insecticides, and as a positive control group, females were exposed to 17.5 mg/L bleomycin under the same experimental conditions. We analyzed three genotoxic parameters, tail length, tail moment, and tail intensity, in ovarian cells. The results showed that 11.2 mg/L Movento® 240SC insecticide significantly increased the tail intensity mean in ovarian cells compared with the negative control. However, 22.4 and 37.3 mg/L Movento® 240SC significantly increased tail length and tail moment means compared with the negative control. Envidor® 240SC insecticide at 12.3, 24.6, 41.1 mg/L significantly increased the three genotoxic parameters in ovarian cells compared with the negative control. The LD50 values of Movento® 240SC and Envidor® 240SC insecticides were 79.1 mg/L and 78.0 mg/L, respectively. The genotoxic response of the two keto-enol pesticides was dependent on the concentration of each pesticide. The results demonstrated that Movento® 240SC and Envidor® 240SC keto-enol insecticides are genotoxic agents in D. melanogaster ovaries.

著者

Tze-Kiong Er Eing-Mei Tsai Li-Yu Tsai Ying-Chin Ko Jau-Nan Lee

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.31, no.1, pp.75-82, 2006 (Released:2006-03-10)

参考文献数

46

被引用文献数

9 9

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Semen samples were obtained from 30 volunteers who had never consumed betel quid. Swim-up spermatozoa from the 30 seminal samples of non-betel quid chewers and also non-smokers, usually not exposed to passive smoking, were treated in vitro with arecoline at different concentrations to evaluate the action of these drugs on sperm motility. Highly motile sperms were collected and divided into 5 equal fractions. Four fractions were supplemented with various concentrations of arecoline and one as control. The study was carried out at time 0 and +1, +2, +3 and +4 hr of incubation. Sperm cells were also extracted and blotted with COX-2 antibody after arecoline treatment after 4 hr incubation. The sperm motility parameters, i.e., motility, average path velocity, curvilinear velocity, straight-line velocity and linearity, were significantly decreased after arecoline treatment. In vitro, arecoline induces the COX-2 expression of sperm cells in a dose-dependent manner. This is the first report to demonstrate that arecoline may mediate COX-2 expression in human sperms, resulting in inflammation response. This situation may act on the structure responsible for the flagellar motion and cause the reduction of sperm motility.

著者

Takako GOTOHDA Aki KUWADA Kyoji MORITA Shin-ichi KUBO Itsuo TOKUNAGA

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.25, no.3, pp.223-231, 2000-08-17 (Released:2008-02-21)

参考文献数

39

被引用文献数

11 12

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Toluene, a commonly used industrial solvent, is known to be toxic to both neuronal and glial cells, and has been shown to increase the immunoreactivity of glial fibrillary acidic protein(GFAP)in the brain. However, the mechanism of toluene-induced GFAP expression is poorly understood. Recently, GFAP mRNA expression in cultured astrocytes has been shown to be modulated by various steroid hormones, such as progesterone, testosterone, and their 5α-reduced metabolites. Therefore, it seems possible that steroid hormones may play a potential role in the enhancement of GFAP expression observed following toluene exposure. To address this possibility, the effect of toluene inhalation on the expression of mRNAs encoding GFAP and steroidogenic enzymes in rat brain was examined. Toluene exposure increased GFAP protein contents without any significant alteration in GFAP mRNA levels in the hippocampus. In contrast, the elevation of both GFAP protein contents and its mRNA levels was observed in the cerebellum following toluene exposure. Further studies indicated that toluene exposure increased steroid 5α-reductase(5α-R)mRNA levels prior to the elevation of GFAP mRNA in the cerebellum, whereas neither 5α-R nor GFAP mRNA levels in the hippocampus were significantly affected by toluene exposure. These results suggest that toluene inhalation may enhance GFAP gene expression in the rat cerebellum, and propose the possibility that the elevation of 5α-R expression, and hence 5α-reduced metabolites of steroid hormones, is presumably related to toluene-induced GFAP mRNA expression.

著者

Misuzu Tanaka Akane Kanasaki Noriko Hayashi Tetsuo Iida Koji Murao

出版者

The Japanese Society of Toxicology

雑誌

Fundamental Toxicological Sciences (ISSN:2189115X)

巻号頁・発行日

vol.8, no.1, pp.23-31, 2021 (Released:2021-04-22)

参考文献数

37

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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.

著者

Ayano Hasegawa Takahiro Sasaki Jahidul Islam Takashi Tominaga Tomonori Nochi Kenshiro Hara Kentaro Tanemura

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.48, no.3, pp.149-159, 2023 (Released:2023-03-01)

参考文献数

32

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Reportedly, antibiotics, which are frequently prescribed in children, have long-term effects owing to gut microbiota dysregulation. Tosufloxacin tosilate hydrate (TFLX) is the first orally administered new quinolone with high efficacy and broad-spectrum action approved as an antibacterial agent for pediatric use in Japan. However, studies on the effects of its early-stage administration are limited. Therefore, we aimed to analyze the later effects of its developmental administration by monitoring growth rate, neurobehavior, and gut microbiota in mice. The TFLX was administered via drinking water at a dose of up to 300 mg/kg for two consecutive weeks during the developmental period (4–6 weeks of age) or adulthood (8–10 weeks of age). Thereafter, the body weights of the mice were measured weekly to monitor growth rate. Behavioral tests were also conducted on 11–12-week-old mice to examine the neurobehavioral effects of the treatment. Further, to examine the effects of the treatment on microbiota, fecal samples were collected from the rectum of mice dissected at 12 weeks of age, and 16s rRNA analysis was conducted. Our results showed increased body weights after TFLX administration, without any long-term effects. Behavioral analysis suggested alterations in anxiety-like behaviors and memory recall dysregulation, and gut microbiota analysis revealed significant differences in bacterial composition. These findings indicated that TFLX administration during the developmental period affects mice growth rate, neurobehavior, and gut microbiota structure. This is the first study to report that TFLX is potentially associated with the risk of long effects.

著者

Atsushi Watanabe Shigeki Yoneyama Mikio Nakajima Norihiro Sato Ryoko Takao-Kawabata Yukihiro Isogai Aki Sakurai-Tanikawa Kazuhiro Higuchi Akihito Shimoi Hideyuki Yamatoya Kenji Yoshida Terutomo Kohira

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.37, no.3, pp.617-629, 2012-06-01 (Released:2012-06-01)

参考文献数

14

被引用文献数

57 69

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Teriparatide, a therapeutic agent for osteoporosis, has been reported to increase the incidences of bone neoplasms such as osteosarcoma when administered subcutaneously to Fischer 344 (F344) rats for a long term, but its non-carcinogenic dose level following 2-year daily administration has not been established. Here we report detailed studies on the carcinogenicity of teriparatide following long-term administration. When teriparatide was administered subcutaneously to male and female Sprague-Dawley (SD) rats daily for 2 years, the incidence of osteosarcoma was increased at 13.6 μg/kg/day. The non-carcinogenic dose level was 4.5 μg/kg/day for both males and females. The development of osteosarcoma in SD rats depends on the dose level of, and treatment duration with, teriparatide. Responses of the bones to teriparatide were similar between F344 and SD rats in many aspects. These results suggested that the carcinogenic potential of teriparatide in SD rats is essentially the same as in F344 rats.

著者

Tomoya Fujie Ayumi Muraoka Keisuke Ito Yusuke Ozaki Chika Yamamoto Toshiyuki Kaji

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.11, pp.493-501, 2022 (Released:2022-11-01)

参考文献数

35

被引用文献数

4

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Lead (Pb) is an environmental pollutant that adversely affects various organs in the human body and is a well-known risk factor for cardiovascular diseases, caused by the dysfunction of vascular endothelial cells that cover the luminal surface of the blood vessels. The Zrt- and Irt-like related protein (ZIP) transporter ZIP8 is one of the primary importers of zinc, iron, manganese, and cadmium, and its expression appears to be important for the metabolism of these metals. In the present study, we investigated the influence of ZIP8 on Pb-induced cytotoxicity in vascular endothelial cells, induction of ZIP8 expression by Pb, and its mechanism of action in vascular endothelial cells. The study revealed the following: (1) Pb cytotoxicity in vascular endothelial cells was potentiated by the knockdown of ZIP8, but the intracellular accumulation of Pb in the cells remain unaffected; (2) Pb induced the expression of ZIP8; (3) the induction of ZIP8 expression by Pb was mediated by nuclear factor (NF)-κB signaling pathway; and (4) Pb activated p38, mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK), but the activation of these MAPKs was not involved in the induction of ZIP8 by Pb. Therefore, the study shows that Pb induces the expression of endothelial ZIP8 and this induction appears to be involved in the protection against Pb cytotoxicity by intracellular Pb accumulation independent mechanisms.

著者

Miho Sakakibara Yosuke Maeda Kazuichi Nakamura

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.8, pp.327-336, 2022 (Released:2022-08-01)

参考文献数

29

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We used an abortion-prone mouse model, generated by mating female CBA/J mice with male DBA/2JJcl mice, to examine the effects of changes in the Th1/Th2 cell ratio and the percentage of regulatory T (Treg) cells on the maintenance of pregnancy. We subcutaneously injected female CBA/J mice once each with 50 μg/mouse of Dermatophagoides farinae (Df) extract and the squalene-based adjuvant (SquA); 10 days later, these mice were mated with male DBA/2JJcl mice. Compared with injection of vehicle or adjuvant, the Df treatment decreased the Th1/Th2 cell ratio and concomitantly increased the percentage of Treg cells in the spleen. In addition, fetal death rates were decreased. We then explored a substance which shifted the Th1/Th2 balance toward Th1 side. We found that 50 μg/mouse of keyhole limpet hemocyanin (KLH) increased the splenic Th1/Th2 cell ratio of nonpregnant female CBA/J mice. We subcutaneously injected female CBA/J mice with KLH and SquA; 10 days later, these mice were mated with male DBA/2JJcl mice. Compared with injection of vehicle or adjuvant, treatment with KLH enhanced the Th1 bias during pregnancy and increased the fetal death rate. The percentage of Treg cells, however, was increased in these KLH-injected pregnant mice contrary to our presumption. All collected data showed strong positive correlation between the Th1/Th2 cell ratio and fetal death rate. The increase in Treg cells independent of effects on the fetal death rate suggests that Treg cells do not necessarily induce maternal tolerance to the fetus but may prevent excessive Th1/Th2 imbalance during pregnancy.

著者

ZheZhe Guan YaLan Li ShaoCong Hu CaiFeng Mo DongLing He Zhi Huang Ming Liao

出版者

The Japanese Society of Toxicology

雑誌

The Journal of Toxicological Sciences (ISSN:03881350)

巻号頁・発行日

vol.47, no.10, pp.389-407, 2022 (Released:2022-09-14)

参考文献数

65

被引用文献数

1

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Trimeresurus stejnegeri is one of the top ten venomous snakes in China, and its bite causes acute and severe diseases. Elucidating the metabolic changes of the body caused by Trimeresurus stejnegeri bite will be beneficial to the diagnosis and treatment of snakebite. Thus, an animal pig model of Trimeresurus stejnegeri bite was established, and then the metabolites of serum and urine were subsequently screened and identified in both ESI+ and ESI- modes identified by ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry (UPLC-Q-TOF-MS) methods. There are 9 differential metabolites in serum, including Oleic acid, Lithocholic acid, Deoxycholic acid, Hypoxanthine, etc. There are 11 differential metabolites in urine, including Dopamine, Thiocysteine, Arginine, Indoleacetaldehyde, etc. Serum enrichment pathway analysis showed that 5 metabolic pathways, including Tryptophanuria, Liver disease due to cystic fibrosis, Hartnup disease, Hyperbaric oxygen exposure and Biliary cirrhosis, the core metabolites in these pathways, including deoxycholic acid, lithocholic acid, tryptophan and hypoxanthine, changed significantly. Urine enrichment pathway analysis showed that 4 metabolic pathways, including Aromatic L-Amino Acid Decarboxylase, Vitiligo, Blue Diaper Syndrome and Hyperargininemia, the core metabolites in these pathways including dopamine, 5-hydroxyindole acetic acid and arginine. Taken together, the current study has successfully established an animal model of Trimeresurus stejnegeri bite, and identified the metabolic markers and metabolic pathways of Trimeresurus stejnegeri bite. These metabolites and pathways may have potential application value and provide a therapeutic basis for the treatment of Trimeresurus stejnegeri bite.