Toshiyuki Shiragiku

Otsuka (Japan)

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Hiroshi Seki

Osaka Metropolitan University

Akiko Koeda

Nagoya City University

Toshiyuki Kudo

Shujitsu University

Shizuyo Sutou

Shujitsu University

Kana Komatsu

Otsuka (Japan)

Takumi Awogi

Otsuka (Japan)

Kinue Ohguro

Otsuka (Japan)

Mika Yamamoto

Teine Keijinkai Hospital

Takehiro Igawa

Otsuka (United States)

Liang Chen

Center for Discovery

Cooperative Institutions

Otsuka (Japan)

Otsuka Pharmaceutical (Spain)

Osaka University

Okayama University

Food and Drug Safety Center

University of Tsukuba

Kyoto University

The University of Tokyo

Tohoku University

Hiroshima University

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Evaluation of In Vivo Mutagenicity by 2,4-Diaminotoluene and 2,6-Diaminotoluene in Liver of F344 gpt delta Transgenic Rat Dosed for 28 Days: A Collaborative Study of the gpt delta Transgenic Rat Mutation Assay

Genes and Environment (2012)

Hajime Sui Ryo Ohta Toshiyuki Shiragiku Ayaka Akahori Kenichiro Suzuki

10.3123/jemsge.34.25

Cite

Citations (6)

Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers association

Genes and Environment (2021)

Atsushi Hakura Takumi Awogi Toshiyuki Shiragiku Atsushi Ohigashi Mika Yamamoto

Abstract Background Ames test is used worldwide for detecting the bacterial mutagenicity of chemicals . In silico analyses of bacterial mutagenicity have recently gained acceptance by regulatory agencies; however, current in silico models for prediction remain to be improved. The Japan Pharmaceutical Manufacturers Association (JPMA) organized a task force in 2017 in which eight Japanese pharmaceutical companies had participated. The purpose of this task force was to disclose a piece of pharmaceutical companies’ proprietary Ames test data. Results Ames test data for 99 chemicals of various chemical classes were collected for disclosure in this study. These chemicals are related to the manufacturing process of pharmaceutical drugs, including reagents, synthetic intermediates, and drug substances. The structure-activity (mutagenicity) relationships are discussed in relation to structural alerts for each chemical class. In addition, in silico analyses of these chemicals were conducted using a knowledge-based model of Derek Nexus (Derek) and a statistics-based model (GT1_BMUT module) of CASE Ultra. To calculate the effectiveness of these models, 89 chemicals for Derek and 54 chemicals for CASE Ultra were selected; major exclusions were the salt form of four chemicals that were tested both in the salt and free forms for both models, and 35 chemicals called “known” positives or negatives for CASE Ultra. For Derek, the sensitivity, specificity, and accuracy were 65% (15/23), 71% (47/66), and 70% (62/89), respectively. The sensitivity, specificity, and accuracy were 50% (6/12), 60% (25/42), and 57% (31/54) for CASE Ultra, respectively. The ratio of overall disagreement between the CASE Ultra “known” positives/negatives and the actual test results was 11% (4/35). In this study, 19 out of 28 mutagens (68%) were detected with TA100 and/or TA98, and 9 out of 28 mutagens (32%) were detected with either TA1535, TA1537, WP2 uvrA, or their combination. Conclusion The Ames test data presented here will help avoid duplicated Ames testing in some cases, support duplicate testing in other cases, improve in silico models, and enhance our understanding of the mechanisms of mutagenesis.

Task force

Ames test

10.1186/s41021-021-00206-1

Cite

Citations (6)

Additional file 1 of Bacterial mutagenicity test data: collection by the task force of the Japan pharmaceutical manufacturers association

Figshare (2021)

Atsushi Hakura Takumi Awogi Toshiyuki Shiragiku Atsushi Ohigashi Mika Yamamoto

Additional file 1.

Task force

Association (psychology)

10.6084/m9.figshare.16714166

Cite

Citations (0)

STUDIES ON THE EFFECT OF CILOSTAZOL ON THE PROSTAGLANDINS PRODUCTION DURING ADP-INDUCED PLATELET AGGREGATION WITH ENDOTHELIAL CELLS

Thrombosis and Haemostasis (1987)

Takashi Chijiwa Toshiyuki Shiragiku Satoshi Kato Takehiro Igawa Yuka Kimura

It has been clinically reported that cilostazol has a potent inhibitory effect on platelet aggregation without changing the prostacyclin level. This study was undertaken to elucidate this clinical effect by a technique developed by us in which platelet aggregation could be evaluated in the presence of cultured endothelial cells. Human umbililical cord vein endothelial cells (HUVEC) were coated (cultured for a few days supplemented with 10% fetal claf serum) on the inner surface of glass cuvette, and platelet aggregation was traced by the stimulation of citrated-PRP with 7.5 μM ADP in this cuvette. The 6-keto-prostaglandin F1α (6-k-PGF) and thromboxane B2 (TXB) produced in the supernatant of the stimulated PRP were measured by radioimmunoassay (Amersham). The cyclic adenosine monophosphate (cAMP) level in platelets and HUVEC was measured by radioimmunoassay (YAMASA). Cilostazol showed a potent inhibitory effect on platelet aggregation in the presence of HUVEC by the suppresion of TXB production, but not by the suppression of 6-k-PGF production. Cilostazol stimulated cAMP production in both platelets and HUVEC. On the other hand, aspirin also showed an inhibitory effect on platelet aggregation in the presence of HUVEC, but suppressed production of both TXB and 6-k-PGF. As a result, the clinical effect of cilostazol was confirmed by the fact that TXA2 production in a platelet/HUVEC coexisting system was specifically suppressed.

Cilostazol

Adenosine diphosphate

10.1055/s-0038-1644465

Cite

Citations (0)

In vitro clastogenicity of optical isomers of nadifloxacin.

PubMed (1994)

Naohiko Takahashi Toshiyuki Shiragiku Tomoo Itoh Emi Kaneko Toshikazu Shibahara

The potential of optical isomers of the fluoroquinolone antibacterial agent nadifloxacin (NDFX, CAS 124858-35-1) to induce chromosomal aberrations in vitro was investigated in cultured Chinese hamster lung (CHL) cells for 24 h of continuous treatment. S- and R-enantiomers of NDFX showed significant differences in the results of the chromosomal aberration test, but no marked differences in the results of cytotoxicity test, i.e., S-NDFX induced chromosomal aberrations, but R-NDFX did not. These results were equivalent to those obtained with ofloxacin (OFLX, CAS 83380-47-6), which has a chemical structure similar to that of NDFX. Moreover, although neither NDFX nor OFLX induced aberrations, their mixtures, prepared from equal amounts of S- and R-enantiomers, did. This finding suggests that the racemic compound and the mixture of S- and R-enantiomers exist under different conditions within the solution.

Chinese hamster

Clastogen

Racemic mixture

Source

Cite

Citations (3)

Correction for Oka et al., “ In Vitro and In Vivo Antibacterial Activities of a Novel Quinolone Compound, OPS-2071, against Clostridioides difficile ”

Antimicrobial Agents and Chemotherapy (2022)

Daisuke Oka Naomitsu Yamaya Takuya Kuno Yuta Asakawa Toshiyuki Shiragiku

Quinolone

Clostridioides

10.1128/aac.02338-21

Cite

Citations (0)

Collaborative study of thresholds for mutagens: Hormetic responses in the micronucleus test and gene induction by mutagenic treatments

Research Square (Research Square) (2023)

Shizuyo Sutou Akiko Koeda Kana Komatsu Toshiyuki Shiragiku Hiroshi Seki

Abstract The linear no-threshold model (LNT) asserts that the genetic effects and carcinogenicity of radiation are proportional to the dose. LNT is also applied to carcinogens and mutagens. However, most experimental data show that the dose-response curve is not linear but rather a J-shaped curve, known as a hormetic response. LNT and hormesis are mutually exclusive. Which is correct? In this study, we investigated dose-response curves of mutagens in the micronucleus test using rodent cells. Since the frequency of background micronuclei was low, detecting a further decrease was difficult. When we conducted a challenge test, where cells were pre-treated with a low dose and post-treated with a high dose, clear hormetic responses were observed. Additionally, during a cross-reaction test, where cells were pre-treated with a low dose of one mutagen and post-treated with a high dose of another mutagen, unequivocal hormetic responses were detected. To investigate gene expression patterns, human lymphoma TK6 cells were treated with mitomycin C, ethyl methanesulfonate, and hydrogen peroxide, and the expression of six genes was examined by RT-PCR. Both GADD45A and p21 genes were induced in a time- and dose-dependent manner. In conclusion, the mutagens used here exhibit hormesis, indicating that the LNT model is invalid.

Hormesis

10.21203/rs.3.rs-3550460/v1

Cite

Citations (0)

Collaborative study of thresholds for mutagens: proposal of a typical protocol for detection of hormetic responses in cytotoxicity tests

Genes and Environment (2018)

Shizuyo Sutou Akiko Koeda Kana Komatsu Toshiyuki Shiragiku Hiroshi Seki

According to the linear no-threshold model (LNT), even the smallest amount of radiation is hazardous. Although the LNT is not based on solid data, this hypothesis has been applied to mutagens and carcinogens. As a result, it has been postulated that there are no thresholds for these chemicals. To demonstrate negativity by experiments is practically impossible, because negative data may leave behind the possibility that additional data might make the resolution power high enough to change negativity to positivity. Furthermore, additional data collection may be endless and we may be trapped in agnosticism. When hormesis is established, in which biological responses are higher at low-doses and lower at high-doses than the control, thresholds could be established between the low- and high-doses. Before examination of thresholds in chemical mutagenesis, hormetic responses in cytotoxicity were tested using cultured mammalian cells.Human cells (HeLa S3 and TK6) or Chinese hamster cells (CHL/IU) were cultured in 96-well plates and treated with mitomycin C (MMC) or ethyl methanesulfonate (EMS) at various dose levels and optical density was measured after addition of a reagent to detect cellular activity. In hormetic responses, data might fluctuate to and fro; therefore, experimental conditions were examined from various aspects to eliminate confounding factors including cell numbers, detection time, the edge effect of 96-well plates, and measurement time after addition of the reagent for detection.The dose response relationship was never linear. Cellular activities after treatment with MMC or EMS were generally higher at lower doses levels and lower at higher doses than the control, showing hormesis and allowing the establishment of thresholds. Dose response curves sometimes showed two or three peaks, probably reflecting different cellular responses.Hormetic responses in cytotoxicity tests were observed and thresholds could be established. Based on the results of this investigation, we put forward a tentative protocol to detect chemical hormesis in cytotoxicity tests, i.e., inoculate 2000 cells per well, add various doses of a test chemical 48 h after inoculation, add a detection dye 10 h after treatment, and measure optical density 2 h after addition of the reagent for detection.

Hormesis

10.1186/s41021-018-0108-1

Cite

Citations (8)

Potentiation of anti-platelet aggregating activity of cilostazol with vascular endothelial cells

Thrombosis Research (1990)

Takehiro Igawa Takeshi Tani Takashi Chijiwa Toshiyuki Shiragiku Seiichi Shimidzu

Cilostazol

10.1016/0049-3848(90)90079-r

Cite

Citations (95)

Collaborative Study of Thresholds for Mutagens: Hormetic Responses in Cell Proliferation Tests Using Human and Murine Lymphoid Cells

Dose-Response (2021)

Shizuyo Sutou Akiko Koeda Kana Komatsu Toshiyuki Shiragiku Hiroshi Seki

We previously showed that hormetic responses can be established in cell activity tests using human and murine adherent cells. This time, we examined whether hormetic responses can be established in cell proliferation tests using suspended human and murine lymphoid cells.Human lymphoblastoid cells (TK6) and mouse lymphoma cells (L5178Y) were cultured in multi-well culture plates and treated with mitomycin C, ethyl methansulfonate, hygromycin B, aclarubicin or colchicine at various dose levels and the number of cells was measured at varied times using a flow cytometer.When the ratio of the number of cells treated with a test chemical to those in the negative control was plotted, the dose-response relationship typically showed a reverse U-shaped curve, indicating the occurrence of hormesis and existence of thresholds in cell toxicity. The hormetic responses depended largely on the test chemical, dose level and exposure time. When examining responses over the course of time, a J-shaped or fallen S-shaped curve was also observed.The dose-response relationship showed a reverse U-shaped curve, a hallmark of hormesis, at least some time points for all chemicals tested here, indicating that chemical hormesis can be established in in vitro cell proliferation tests.

Hormesis

Colchicine

Lymphoblast

10.1177/15593258211028473

Cite

Citations (4)