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Journal of Toxicological Sciences

Hidemi Mochizuki, Naoya Murota, Shin-Ichi Sato, Kazuo Nii, Yoko Kouhei, Masahiro Taniguchi, Ryo Inoue, Chiyoko Nishime, Hideki Tsutsumi
We investigated the viability of a combined repeated dose toxicity study, including toxicokinetics (TK), in common marmosets according to the ICH-S4, ICH-S3A and ICH-S7A Guidelines using valsartan as test article whose non-clinical repeated dose toxicity studies had been conducted using this species for regulatory purpose. Valsartan was administered orally to 3 animals/sex at 200 mg/kg/day for 2 weeks. In addition to the routine parameters in repeated dose toxicity studies, safety pharmacology parameters (examinations of the central nervous, respiratory and cardiovascular systems) were also evaluated...
2018: Journal of Toxicological Sciences
Ana Mara Islas-Espinoza, Carolina Campos-Rodriguez, Eduardo Ramírez San Juan
Thalidomide was originally developed to treat primary neurological and psychiatric diseases. There are reports of anticonvulsant effects of thalidomide in rats and antiepileptic effects in patients. Hence, thalidomide (100, 200 and 400 mg/kg) was herein administered to mice to evaluate possible protection against seizures induced by the systemic administration of neurotoxins: 10 mg/kg of 4-aminopyridine (4-AP), 90 mg/kg of pentylenetetrazol (PTZ), or 380 mg/kg of pilocarpine. The effect of an NO and COX inhibitor (7-NI and ibuprofen, respectively) was also examined...
2018: Journal of Toxicological Sciences
Guigang Yan, Lianzhi Yu, Songmei Jiang, Jianfeng Zhu
High energy-consumption in retinal pigmented epithelium (RPE) cells poses oxidative stress (OS) and contributes to mitochondrial dysfunction (MD) for retinal degeneration-associated diseases. In the present study, we evaluated the protective role of Melatonin, a natural antioxidant, against the hydrogen peroxide (H2 O2 )-induced damage to RPE cells. The cellular viability, apoptosis, the expression of apoptosis-associated proteins and mitochondrial function were examined in the retinal ARPE-19 cells, post the treatment with H2 O2 or (and) with Melatonin...
2018: Journal of Toxicological Sciences
Li Xiong, Hao Liyue, Zeng Fancai, Li Maoting, Li Ya, He Ting, Yang Zhen, Zhu Shanshan, Gu Wenwen, Tang Yan
Previous studies have reported the potential developmental neurobehavioral effects of decabrominated diphenyl ethers (BDE 209) on developing animals, but the effects on adult animals are rare or controversial and the mechanism is not fully understood. In the present study, male adult Sprague-Dawley rats performed poor spatial learning and memory in Morris water maze after exposure to BDE 209 by gavage for 30 days. The expression of hippocampal glutamate receptor subunits NR1, NR2B and GluR1, the phosphorylation of NR2B subunit at Ser1301 (p-NR2B Ser1303) and GluR1 subunit at Ser831 (p-GluR1 Ser831) were all decreased, and the phosphorylation ratio of NR2B revealed an increasing trend after BDE 209 exposure...
2018: Journal of Toxicological Sciences
Tin-Tin Win-Shwe, Nay Chi Nway, Motoki Imai, Thet-Thet Lwin, Ohn Mar, Hidehiro Watanabe
Autism is a complex neurodevelopmental disorder characterized by impaired social communication and social interactions, and repetitive behaviors. The etiology of autism remains unknown and its molecular basis is not yet well understood. Pregnant Sprague-Dawley (SD) rats were administered 600 mg/kg of valproic acid (VPA) by intraperitoneal injection on day 12.5 of gestation. Both 11- to 13-week-old male and female rat models of VPA-induced autism showed impaired sociability and impaired preference for social novelty as compared to the corresponding control SD rats...
2018: Journal of Toxicological Sciences
Liyun He, Zhenying Chen, Bo Dai, Guilin Li, Gaochun Zhu
Lead exposure contributing to cardiovascular diseases is known and recognized widely. As the deleterious effects of low lead exposure attained increasing attention over the last decades, there have been numerous studies exploring the association of low levels of lead exposure and cardiovascular diseases. Moreover, it has been observed that lead exposure could cause telomere shortening and lipid disturbance, and that telomere shortening and lipid disturbance are closely related with cardiovascular diseases. Hence, telomere shortening and lipid disturbance might play an important role in the pathophysiological process of chronic low levels of lead exposure contributing to cardiovascular diseases...
2018: Journal of Toxicological Sciences
Misato Nakamura, Ayumi Eguchi, Mari Inohana, Rei Nagahara, Hirotada Murayama, Masashi Kawashima, Sayaka Mizukami, Mihoko Koyanagi, Shim-Mo Hayashi, Robert R Maronpot, Makoto Shibutani, Toshinori Yoshida
Mineralocorticoid receptor (MR)/NADPH oxidase (NOX) signaling is involved in the development of obesity, insulin resistance, and renal diseases; however, the role of this signaling on steatotic preneoplastic liver lesions is not fully elucidated. We determined the effects of the MR antagonist potassium canrenoate (PC) on MR/NOX signaling in hepatic steatosis and preneoplastic glutathione S-transferase placental form (GST-P)-positive liver foci. Rats were subjected to a two-stage hepatocarcinogenesis model and fed with basal diet or high fat diet (HFD) that was co-administered with PC alone or in combination with the antioxidant alpha-glycosyl isoquercitrin (AGIQ)...
2018: Journal of Toxicological Sciences
Hisakuni Obayashi, Naoko Kobayashi, Yoshikazu Nezu, Takashi Yamoto, Mitsuyuki Shirai, Fumitoshi Asai
Previously, we have demonstrated the potential of plasma 2-hydroxyglutarate (2HG) as an easily detectable biomarker for skeletal muscle injury in rats. Here, we examined whether plasma 2HG was superior to conventional skeletal muscle damage biomarkers, including aspartate aminotransferase (AST), creatine kinase (CK), and skeletal muscle-type CK isoenzyme (CK-MM) levels, in rats. Skeletal muscle injury was induced in 4- or 9-week-old male Fischer 344 rats by cerivastatin (CER) or tetramethyl-p-phenylenediamine (TMPD) administration...
2018: Journal of Toxicological Sciences
Yoshimitsu Sakamoto, Motoki Hojo, Yuki Kosugi, Kimiyo Watanabe, Akihiko Hirose, Akiko Inomata, Toshinari Suzuki, Dai Nakae
The present study comparatively examined carcinogenicity of 7 different multi-wall carbon nanotubes (MWCNTs) with different physicochemical characteristics. Physicochemical characteristics of MWCNTs (referred to as M-, N-, WL-, SD1-, WS-, SD2- and T-CNTs in the present study) were determined using scanning electron and light microscopes and a collision type inductively coupled plasma mass spectrometer. Male Fischer 344 rats (10 weeks old, 15 animals per group) were administered MWCNTs at a single intraperitoneal dose of 1 mg/kg body weight, and sacrificed up to 52 weeks after the commencement...
2018: Journal of Toxicological Sciences
Joana Feiteiro, Melissa Mariana, Solage Glória, Elisa Cairrao
Bisphenol A (BPA) is an endocrine disrupting chemical used on a wide range in industry. This compound has been used in the production of polycarbonate plastics and epoxy resins. For this reason and their global use, BPA is one of the most common environmental chemicals to which humans are exposed. This exposure can cause several adverse health outcomes, including at the cardiovascular level. The regulation of ion channels in vascular smooth muscle is pivotal and important for vasoreactivity, and changes in their flux can be involved in the pathophysiology of some cardiovascular diseases...
2018: Journal of Toxicological Sciences
Jon C Cook, Hong Wu, Michael D Aleo, Karissa Adkins
Precision medicine is an approach to developing drugs that focuses on employing biomarkers to stratify patients in clinical trials with the goal of improving efficacy and/or safety outcomes, ultimately increasing the odds of clinical success and drug approval. Precision medicine is an important tool for toxicologists to utilize, because its principles can be used to decide whether to pursue a drug target, to understand interindividual differences in response to drugs in both nonclinical and clinical settings, to aid in selecting doses that optimize efficacy or reduce adverse events, and to facilitate understanding of a drug's mode-of-action...
2018: Journal of Toxicological Sciences
Shuji Ogawa, Hiroyuki Kuroda, Toshiko Kinomoto, Yoshihiro Kawabata, Mayumi Kawabe, Mayuko Suguro, Yuji Oishi
There is sometimes controversy over whether or not statistically significant responses produced in carcinogenicity studies have biologically significance. Ambiguous results from our previous two-year oral carcinogenicity study on acotiamide hydrochloride hydrate (acotiamide-HH), a prokinetic drug for functional dyspepsia, in rats made it unclear whether the drug may exhibit uterine carcinogenicity. To check this finding, we performed a second long-term carcinogenicity study using two identical control groups to more accurately evaluate uterine carcinogenesis by considering the incidence of spontaneous neoplasms...
2018: Journal of Toxicological Sciences
Yongmin Xu, Dazhuang Sun, Chunqing Song, Rui Wang, Xuesong Dong
OBJECTIVE: To investigate the protective effect and underlying mechanism of the superoxide dismutase mimic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP), on paraquat (PQ)-induced lung alveolar epithelial-like cell injury. METHODS: Lung alveolar epithelial-like cells (A549) were pretreated with 10 μM MnTMPyP for 1.5 hr and then cultured with or without PQ (750 uM) for 24 hr. Cell survival was determined using the MTT assay. Apoptosis, mitochondrial transmembrane potential, reactive oxygen species (ROS) production, and Ca2+ levels were measured using flow cytometry...
2018: Journal of Toxicological Sciences
Masayo Hirao-Suzuki, Shuso Takeda, Takanobu Kobayashi, Katsuhito Kino, Hiroshi Miyazawa, Michael P Waalkes, Masufumi Takiguchi
There is adequate evidence for the carcinogenicity of cadmium (Cd). However, a significant unaddressed question remains as to how this metal actually causes malignant transformation (tumor initiation). Since it has been shown that Cd only has the weak direct interaction potential with DNA, the metal is recognized as an indirect genotoxicant and mutagen. Currently, Cd-mediated "epigenetic" modifications, such as changes in DNA methylation resulting in alteration in target gene expression, coupled with cancer progression, are the focus of mechanistic research...
2018: Journal of Toxicological Sciences
Tetsuya Fujimoto, Shuji Aou
Perinatal exposure to bisphenol A (BPA) causes several alterations in brain function and behavior. In previous studies, we showed that prenatal treatment with low-level BPA impaired gender-specific behavior, enhanced depression-like behavior, and augmented behavioral responses to predator odor in rats. On this premise, we hypothesized that BPA-treated rats were more susceptible to predator odor stress. To test the potential neural mechanism underlying this effect, we conducted an electrophysiological study of neurons in the medial amygdala-a regional component of the olfactory pathway with high estrogen and androgen receptor expression, and thus a potential target of BPA-in rats exposed to BPA...
2018: Journal of Toxicological Sciences
Ryuji Watari, Motoharu Kakiki, Ayumi Oshikata, Toshiaki Takezawa, Chihiro Yamasaki, Yuji Ishida, Chise Tateno, Yukie Kuroda, Seiichi Ishida, Kazutomi Kusano
During drug discovery, in vitro models are used to predict the in vivo pharmacokinetic and toxicological properties of drug candidates in humans. However, the conventional method of culturing human hepatocytes as monolayers does not necessarily replicate biologic reactions and does not support liver-specific functions, such as cytochrome P450 (CYP) activities, for prolonged periods. To remedy these problems and thus increase and prolong hepatic functions, we developed a culture system comprising a collagen vitrigel membrane (CVM) chamber and PXB-cells®, fresh hepatocytes isolated from liver-humanized chimeric mice (PXB-mice®)...
2018: Journal of Toxicological Sciences
Kunihiko Yamashita, Hiroshi Miyazaki, Shinsuke Shinoda, Saori Hagiwara, Hirohito Takahashi, Hiroshi Itagaki
We evaluated the skin sensitizing potential of 10 natural organic chemicals, or their derivatives, which are included in foods and/or skin products, using a modified local lymph node assay (LLNA), with an elicitation phase (LLNA:DAE). The following compounds were tested: carminic acid, esculetin, 4-methyl esculetin, coumarin, quercetin, curcumin, naringenin, chlorogenic acid, isoscopoletin, and shikonin. Esculetin, 4-methyl esculetin, isoscopoletin, and shikonin yielded positive results. In particular, shikonin at a very low concentration (0...
2018: Journal of Toxicological Sciences
Nur Jaharat Lubna, Yuji Nakamura, Mihoko Hagiwara-Nagasawa, Ai Goto, Koki Chiba, Kumiko Kitta, Hiroko Izumi-Nakaseko, Kentaro Ando, Atsuhiko T Naito, Yasuki Akie, Atsushi Sugiyama
We analyzed electropharmacological characteristics of microminipigs under halothane-anesthesia using anti-influenza virus drug oseltamivir, which has been known to possess multi-channel blocking properties, including Na+ , Ca2+ and K+ channels (n = 4). Oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously infused over 10 min with an interval of 20 min, which provided peak plasma concentrations 1.4, 7.4 and 125.5 µg/mL, respectively. The low dose did not alter any of the cardiovascular variables. The middle dose decreased the heart rate at 30 min after the start of the infusion...
2018: Journal of Toxicological Sciences
Takehito Isobe, Masaki Honda, Ryuichi Komatsu, Mitsuyasu Tabo
We used motion field imaging to characterize the conduction and contraction of a sheet of cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs). A hiPS-CMs sheet of 2.8 mm × 2.8 mm allowed us to simultaneously measure the conduction and the contraction properties in the same cells. Pharmacological responses in the hiPS-CMs of four typical cardiac functional modulators, Na+ channel blocker (lidocaine), Ca2+ channel blocker (diltiazem), gap-junction inhibitor (carbenoxolone), and β-adrenergic stimulator (isoproterenol), were investigated, and the results were compared to those found using the isolated guinea-pig heart model perfused by the Langendorff method...
2018: Journal of Toxicological Sciences
Min-Seok Kim, Jin-Young Han, Sung-Hwan Kim, Hyung-Young Kim, Doin Jeon, Kyuhong Lee
Polyhexamethylene guanidine phosphate (PHMG) is an antimicrobial biocide that causes severe lung injury accompanied with inflammation and subsequent fibrosis. Cytokines mediate the inflammatory response, leading to fibrosis in injured tissues. PHMG is known to induce the expression of various cytokines in vitro and in vivo. In the present study, we investigated the involvement of three MAPK subfamilies (JNK, p38 MAPK, and ERK) in PHMG-induced cytokine expression in A549 human lung epithelial cells. Our in vivo and in vitro data indicated that PHMG induced an increase in mRNA expression of IL-6 and TNF-α, and enhanced the phosphorylation of JNK, p38 MAPK, and ERK...
2018: Journal of Toxicological Sciences
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