The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
ISSN-L : 0388-1350
Current issue
Displaying 1-7 of 7 articles from this issue
Original Article
  • Teppei Hayama, Rin Sugawara, Ryo Kamata, Masakazu Sekijima, Kazuki Tak ...
    2025 Volume 50 Issue 7 Pages 309-324
    Published: 2025
    Released on J-STAGE: July 01, 2025
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    Identifying the molecular targets of toxic compounds remains a major challenge in toxicology, particularly when adverse effects occur in off-target organs and the mechanism of action is unknown. To address this issue, a comprehensive computational pipeline was developed to perform high-throughput molecular docking across the entire AlphaFold2-predicted structural proteome of representative organisms such as human and mouse, followed by enrichment analysis to estimate biological processes potentially affected by ligand binding. The pipeline was first evaluated using six known drug–target pairs. In several cases, the known targets were ranked between the top 2 and 250 proteins (top 0.009–1.15%) among more than 21,000 proteins, and displayed docking poses consistent with experimentally observed binding conformations. However, performance was limited for certain targets, such as carbonic anhydrase II with acetazolamide, where the binding pocket was broad, leading to inaccurate docking results. The pipeline was subsequently applied to puberulic acid, a compound suspected of causing severe nephrotoxicity. Screening identified sodium/myo-inositol cotransporter 2 (SLC5A11) as a high-affinity target in both human and mouse, suggesting a mechanism involving disruption of renal osmoregulation. Although docking scores represent only theoretical binding estimates and do not directly imply physiological effects, their distribution was independent of protein length and AlphaFold2 confidence scores (pLDDT), supporting the methodological robustness. This in silico framework enables hypothesis-driven identification of potential target proteins for toxicants or therapeutics and offers a useful tool for predictive toxicology, particularly when experimental data are limited. The pipeline is available at: https://github.com/toxtoxcat/reAlldock.

Original Article
  • Yoshikazu Yamagishi, Hiroyuki Inoue, Sayaka Nagasawa, Hirotaro Iwase, ...
    2025 Volume 50 Issue 7 Pages 325-332
    Published: 2025
    Released on J-STAGE: July 01, 2025
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    Amlodipine (AM), a dihydropyridine calcium channel blocker, is frequently prescribed for hypertension in the clinical setting. Because AM has been detected in various lethal poisoning and suicide cases, it is important to determine its precise concentration in postmortem blood to serve as definitive evidence of death by intoxication. However, blood AM concentration at autopsy frequently differs from that at the time of death. In this study, we found that AM undergoes dehydrogenation by H2O2 at temperatures ranging from 4 to 45ºC. Mass spectra measured by quadrupole-Orbitrap mass spectrometry hyphenated with liquid chromatography showed the generation of 3-ethyl 5-methyl 2-((2-aminoethoxy)methyl)-4-(2-chlorophenyl)-6-methylpyridine-3,5-dicarboxylate (AM-PDP-1) in H2O2 and Hb/H2O2 reaction solutions incubated with AM and in postmortem blood of persons who died of drowning, fire, disease, drug poisoning, CO poisoning, traumatic shock, falling, or choking, after intentional ingestion of AM. AM-PDP-1 is the novel postmortem degradation compound of AM in blood. This compound in the Hb/H2O2 reaction solution was more stable than AM at 4–45ºC. These results show that AM-PDP-1, formed by H2O2-mediated postmortem AM decomposition, is a potential biomarker to correct for AM concentration in postmortem blood.

Original Article
  • Hideki Hanada, Seigo Sanoh, Keiko Kashiwagi, Akihiko Kashiwagi
    2025 Volume 50 Issue 7 Pages 333-342
    Published: 2025
    Released on J-STAGE: July 01, 2025
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    Supplementary material

    One of the cancer drugs discharged into hospital wastewater, doxorubicin (DOX), is suspected of toxic effects on aquatic organisms. Cardiac and mitochondrial toxicity of DOX was investigated using cultured Xenopus (X.) laevis tadpole heart and mature frog liver mitochondria as materials. While 10-9 DOX was not found to suppress heart rate, 10-7 M DOX caused short-term heartbeat suppression in a preliminary experiment. Compared to the heart rate of untreated organ hearts kept in heart-organ medium without hydrogen-peroxide oxidoreductase enzyme catalase (CAT) for 9 days, that of 10-8 M DOX-treated hearts decreased over time. The heartbeat suppression was improved by adding CAT to the heart culture medium, suggesting that DOX induces reactive oxygen species (ROS) in cultured tadpole hearts. Mitochondrial swelling assay was conducted. DOX was found to suppress slight swelling of heart and liver mitochondria with adenosine triphosphate (ATP) treatment. DOX also suppressed Ca++-induced swelling of heart and liver mitochondria with ATP treatment. These findings suggest that the side effects of DOX on X. laevis heart and liver mitochondria are likely similar to those of cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MPT) and also a ROS generator, leading to cardiac and mitochondrial dysfunction.

Original Article
  • Kinuko Uno, Keita Sekiguchi, Noriko Suzuki-Kemuriyama, Takeshi Ohta, K ...
    2025 Volume 50 Issue 7 Pages 343-350
    Published: 2025
    Released on J-STAGE: July 01, 2025
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Nonalcoholic fatty liver disease (NAFLD) is a lifestyle-related disease. A gut-liver axis is involved in the progression of NAFLD. Disruption of the intestinal barrier function is an exacerbating factor of NAFLD. In this study, we have investigated the interaction between colitis and NAFLD in mouse models of dextran sodium sulfate (DSS)-induced colitis and diet-induced NAFLD-like lesions. Male C57BL/6J mice were provided with a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) and 1.25% DSS water for 3 weeks. The DSS water was administered intermittently. In the large intestine, the DSS-treated groups clearly demonstrated inflammation. Dilation of crypt and goblet cells was observed in the DSS + CDAHFD group. The expression of minor inflammation-related genes was increased in the CDAHFD group. In the liver, the CDAHFD group demonstrated non-alcoholic steatohepatitis (NASH)-like lesions. The number of C-X-C motif chemokine ligand 16 (CXCL16)-positive cells increased in the CDAHFD group and tended to increase in the DSS + CDAHFD group. Toll-like receptor 4 (TLR4)-positive cells were observed mainly in gallbladder epithelial cells in all groups and were more pronounced in the DSS-administered groups. Inflammation-related genes were upregulated in the DSS group. The expression of fibrosis-related genes increased in the DSS + CDAHFD group. DSS-induced colitis and CDAHFD-induced NASH interacted with each other. NAFLD lesions were induced by CDAHFD and exacerbated by TLR4 and CXCL16 in DSS-induced colitis. Colitis is induced by DSS and exacerbated by changes in the intestinal environment due to liver injury. This combined model was useful in analyzing early lesions of liver-gut axis for NAFLD.

Letter
  • Yutaro Yamada, Ryo Ito, Takuya Noguchi, Shuhei Hamano, Kohei Otani, Ta ...
    2025 Volume 50 Issue 7 Pages 351-359
    Published: 2025
    Released on J-STAGE: July 01, 2025
    JOURNAL FREE ACCESS FULL-TEXT HTML

    It is well known that apoptosis is triggered by arsenic. Meanwhile, recent evidence has demonstrated that arsenic also induces a non-canonical form of regulated cell death (RCD) called parthanatos that is triggered by the overactivation of poly (ADP-ribose) polymerase-1 (PARP-1). Here, we provide evidence of a novel mechanistic link between parthanatos and apoptosis induced by arsenic. Exposure to sodium arsenite clearly induced parthanatos in typical cancer cell lines such as HeLa and HT1080 cells, without activation of the apoptotic cascade, including the caspase-3 activation. Of note, we observed aggregation of caspase-3 in response to sodium arsenite, which was abolished by treatment with 4-phenylbutyrate (4-PBA), a chemical chaperone that prevents protein aggregation. Interestingly, in the presence of 4-PBA, sodium arsenite induced apoptosis rather than parthanatos. These findings suggest that the disaggregation of caspase-3 allows arsenic to induce the caspase-3 activation, and subsequent apoptosis. Thus, our results show that the degree of the caspase-3 aggregation may be a critical determinant of the selectivity of sodium arsenite-induced cell death.

Original Article
  • Ayun Seol, Ji Eun Kim, Hee Jin Song, Tae Ryeol Kim, Eun Seo Park, Ki H ...
    2025 Volume 50 Issue 7 Pages 361-378
    Published: 2025
    Released on J-STAGE: July 01, 2025
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    The internalization mechanism of microplastics (MPs) into human cells has attracted considerable attention because these mechanisms are closely related to the physical and chemical properties of MPs. This study examined the response of human colon cells to autophagy, ER stress, and inflammation during the regulation on the internalization of polystyrene (PS)-MPs (0.4-0.6 μm size). To achieve this, changes in their key markers were analyzed in MPs-treated SNU-1826 cells after a cotreatment with uptake inhibitors or stimulators. The internalization of MPs was significantly higher in SNU-1826 cells than in other cells originated from differential tissues, such as the small intestine, kidneys, and nerves. On the other hand, the internalization of MPs into SNU-1826 cells was suppressed by cytochalasin D (CD) but not by pitstop (Pt). During this inhibition, the levels of the key parameters for autophagy (Light Chain 3-I/II (LC3-I/II) and Beclin1), ER stress (eukaryotic translation initiation factor 2 subunit alpha (EIF2α) and inositol-requiring kinase 1 alpha (IRE1α)), and inflammation (inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-α), and interleukin (IL)-6) were suppressed in MPs+CD-treated SNU-1826 cells. In addition, the internalization of MPs into SNU-1826 cells was stimulated by a ZnSO4 treatment, not by CaCl2. These stimulation effects were reflected in the alteration of the critical parameters for autophagy, ER stress, and inflammation. Furthermore, the positive correlation was detected between MPs internalization and most parameters for cellular responses although their inhibition is stronger than stimulation. These results suggest that the internalization of MPs into SNU-1826 cells may be strongly associated with the changes in autophagy, ER stress, and inflammation during the regulation of CD and ZnSO4.

Retraction
  • Ji Zhang, Wen Chai, Zhengbing Xiang, Xinhua Zhou, Ping Zhang
    2025 Volume 50 Issue 7 Pages R2-
    Published: 2025
    Released on J-STAGE: July 11, 2025
    JOURNAL FREE ACCESS

    Editor’s Announcement


    MZF1 alleviates oxidative stress and apoptosis induced by rotenone in SH-SY5Y cells by promoting RBM3 transcription

    Ji Zhang, Wen Chai, Zhengbing Xiang, Xinhua Zhou, Ping Zhang

    (The Journal of Toxicological Sciences, 46, 477-486, 2021)


    This paper has been withdrawn at the request of the authors.


    This article was accepted for publication by the Editorial Committee of The Journal of Toxicological Sciences after a regular peer review process. However, the Editorial Committee received an email from the corresponding author, Dr. Ping Zhang, requesting that the paper be withdrawn. The Editorial Board asked him to submit a letter of consent from all co-authors, and he subsequently provided one with the signatures of all co-authors. As that letter attested to the authors' intention, we approved the withdrawal of this paper.


    The authors have not disclosed the reasons for the withdrawal. However, the Editorial Committee has decided to respect their decision. Therefore, this action was taken at the authors' own responsibility.


    Toshiyuki Kaji, Ph.D.

    Editor-in-Chief

    The Journal of Toxicological Sciences

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