Fundamental Toxicological Sciences

2021 - Vol. 8 No. 3

2021 - Vol. 8

Original Article
Inorganic polyphosphate modulates leukocyte accumulation and vascular endothelial cell permeability and ameliorates cecal ligation and puncture-induced lethality Vol.8, No.3, p.89-96
Yoshitaka Yamazaki , Mikako Terashima-Hasegawa , Atsufumi Manabe , Toshikazu Shiba , Yumi Kawazoe , Takashi Ashino , Masahiro Hosonuma , Satoshi Numazawa
Released: July 27, 2021
Abstract Full Text PDF[1004K]

Inorganic polyphosphates with an average degree of polymerization of 150 (polyP150) have been shown to improve mortality in a lipopolysaccharide model of sepsis in mice. We aimed to investigate the effects of polyP150 in a mouse model of cecal ligation and puncture (CLP) peritonitis, which accurately reflects clinical sepsis, and elucidate its mechanism of action and suitability as a candidate for sepsis treatment. The present study demonstrated that treatment with polyP150 significantly improved survival rate in mouse model of CLP peritonitis. polyP150 inhibited a CLP-mediated increase in pulmonary vascular permeability as demonstrated by Evans blue dye assay. Pretreatment of polyP150 in human vascular endothelial cells, HMEC-1 cells, showed inhibition of tumor necrosis factor-α-induced monocytic THP-1 cell adhesion and intercellular adhesion molecule 1/CD54 gene expression. These results suggest that polyP150 ameliorates fatal sepsis by inhibiting expression of the cell adhesion molecule and the accumulation of leukocytes in the vascular endothelium, thereby suppressing the increase in vascular permeability. Our results in this study suggest that polyP150 could be a candidate for novel sepsis treatments.

Data Report
Movento® 240SC (Spirotetramat) and Envidor® 240SC (Spirodiclofen) keto-enol insecticides induce DNA damage in Drosophila melanogaster ovaries Vol.8, No.3, p.81-88
Berenyce González-Marín , María Elena Calderón-Segura , Ana Karen González Pérez , Luis Gerardo Moreno Ciénega
Released: July 27, 2021
Abstract Full Text PDF[923K]

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.

Original Article
Effects of the ethanol extract of Neopyropia yezoensis, cultivated in the Seto Inland Sea (Setonaikai), on the viability of 10 human cancer cells including endocrine therapy-resistant breast cancer cells Vol.8, No.3, p.75-80
Shuso Takeda , Masayo Hirao-Suzuki , Yukimasa Yamagishi , Takahiro Sugihara , Masataka Kaneko , Genki Sakai , Tetsuya Nakamura , Yuhzo Hieda , Masufumi Takiguchi , Masahiro Okada , Narumi Sugihara
Released: June 23, 2021
Abstract Full Text PDF[1M]

Here, we established an ethanol extraction method and obtained extracts of Neopyropia yezoensis cultivated in three different locations (extracts A-C) in the Seto Inland Sea (Setonaikai). The effects of the extracts on 10 human cancer cells derived from seven different organs were investigated. Extract A exerted the strongest anti-proliferative effects on all types of cancer cells, including an endocrine therapy-resistant aggressive breast cancer model, LTED cells. We analyzed the effects of the extracts on MCF-7 (parental cells for producing LTED cells)/LTED cells, along with four established anti-proliferative agents (etoposide, LY2835219, paclitaxel, and trichostatin A) with different action mechanisms. The inhibitory effects of extract A on both breast cancer cells were comparable with those of paclitaxel, although the other agents showed a preferable reduction in MCF-7 cell viability. We provide evidence of the involvement of component(s), especially those of extract A of N. yezoensis, which exerted anti-proliferative effects on cancer cells.

Evaluation of the in vitro cytotoxicity of oscillatoxins E and F under nutrient-starvation culture conditions Vol.8, No.3, p.69-73
Yusuke Hanaki , Yusuke Araki , Toshio Nishikawa , Ryo C. Yanagita
Released: June 15, 2021
Abstract Full Text PDF[1M]

Oscillatoxins E (1) and F (2) are cyanotoxins isolated from cyanobacteria in the genus Lyngbya. We recently reported the first total synthesis of these compounds and determined their cytotoxicity in various cancer cell lines. Their anti-proliferative activities were moderate, but 2 exhibited unique cell line selectivity. In order to understand their mode of action, in this study we evaluated the cytotoxicity of 1 and 2 under nutrient-depletion culture conditions. Interestingly, 2 exhibited stronger cytotoxicity in HHUA endometrial cancer cells, especially under FBS-starvation conditions. However, its toxicity was not increased in HHUA cells precultured in FBS-depleted medium. These results suggest that 2 is not selectively toxic to nutrient-starved cells and that FBS components such as albumin more strongly neutralized the cytotoxicity of 2 relative to 1. The protein composition of FBS varies by production lot, and the amount of FBS supplemented to culture medium is flexibly determined depending upon the cell line used and experimental objectives. Therefore, it is important to consider the detoxification activity of FBS to precisely evaluate the properties of oscillatoxins, including cytotoxic potency, cell line selectivity, and their respective structure–activity relationships.