DTox: A deep neural network-based in visio lens for large scale toxicogenomics data
J Toxicol Sci. 2024;49(3):105-115. doi: 10.2131/jts.49.105.ABSTRACTWith the advancement of large-scale omics technologies, particularly transcriptomics data sets on drug and treatment response repositories available in public domain, toxicogenomics has emerged as a key field in safety pharmacology and chemical risk assessment. Traditional statistics-based bioinformatics analysis poses challenges in its application across multidimensional toxicogenomic data, including administration time, dosage, and gene expression levels. Motivated by the visual inspection workflow of field experts to augment their efficiency of screening...
Source: Journal of Toxicological Sciences - March 3, 2024 Category: Toxicology Authors: Takeshi Hase Samik Ghosh Ken-Ichi Aisaki Satoshi Kitajima Jun Kanno Hiroaki Kitano Ayako Yachie Source Type: research
Developing a GNN-based AI model to predict mitochondrial toxicity using the bagging method
J Toxicol Sci. 2024;49(3):117-126. doi: 10.2131/jts.49.117.ABSTRACTMitochondrial toxicity has been implicated in the development of various toxicities, including hepatotoxicity. Therefore, mitochondrial toxicity has become a major screening factor in the early discovery phase of drug development. Several models have been developed to predict mitochondrial toxicity based on chemical structures. However, they only provide a binary classification of positive or negative results and do not provide the substructures that contribute to a positive decision. Therefore, we developed an artificial intelligence (AI) model to predict ...
Source: Journal of Toxicological Sciences - March 3, 2024 Category: Toxicology Authors: Yoshinobu Igarashi Ryosuke Kojima Shigeyuki Matsumoto Hiroaki Iwata Yasushi Okuno Hiroshi Yamada Source Type: research
Discovery and development of COVID-19 vaccines and therapeutics: nonclinical perspectives
J Toxicol Sci. 2024;49(3):79-94. doi: 10.2131/jts.49.79.ABSTRACTThe development and regulatory review of BNT162b2, a COVID-19 vaccine, and PaxlovidTM (nirmatrelvir tablets/ritonavir tablets), a COVID-19 therapeutic, are benchmarks for accelerated innovation during a global pandemic. Rapid choice of the SARS-CoV-2 spike protein and main protease (Mpro) as targets for the vaccine and therapeutic, respectively, leveraged the available knowledge of the biology of SARS-CoV-2 and related viruses. The nonclinical immunogenicity and safety of BNT162b2 was rigorously assessed. Likewise, a comprehensive nonclinical safety assessment...
Source: Journal of Toxicological Sciences - March 3, 2024 Category: Toxicology Authors: Nasir Khan Jean Sathish Cynthia M Rohde Source Type: research
Possible nonimmunological toxicological mechanisms of vesnarinone-associated agranulocytosis in HL-60 cells: role of reduced glutathione as cytotoxic defense
In conclusion, we present the first demonstration of the cytotoxic effects and ROS production resulting from the MPO/H2O2/Cl- metabolic reaction of vesnarinone and newly identified the causative metabolite, M2, as the N-chloramine metabolite of M1, which induces cytotoxicity in HL-60 cells. Moreover, a protective role of GSH against the cytotoxicity was revealed. These findings suggest a possible nonimmunological cause of vesnarinone agranulocytosis.PMID:38432956 | DOI:10.2131/jts.49.95 (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - March 3, 2024 Category: Toxicology Authors: Toshihisa Koga Yuko Sahara Tadaaki Ohtani Kaneko Yosuke Ken Umehara Source Type: research
DTox: A deep neural network-based in visio lens for large scale toxicogenomics data
J Toxicol Sci. 2024;49(3):105-115. doi: 10.2131/jts.49.105.ABSTRACTWith the advancement of large-scale omics technologies, particularly transcriptomics data sets on drug and treatment response repositories available in public domain, toxicogenomics has emerged as a key field in safety pharmacology and chemical risk assessment. Traditional statistics-based bioinformatics analysis poses challenges in its application across multidimensional toxicogenomic data, including administration time, dosage, and gene expression levels. Motivated by the visual inspection workflow of field experts to augment their efficiency of screening...
Source: Journal of Toxicological Sciences - March 3, 2024 Category: Toxicology Authors: Takeshi Hase Samik Ghosh Ken-Ichi Aisaki Satoshi Kitajima Jun Kanno Hiroaki Kitano Ayako Yachie Source Type: research
Developing a GNN-based AI model to predict mitochondrial toxicity using the bagging method
J Toxicol Sci. 2024;49(3):117-126. doi: 10.2131/jts.49.117.ABSTRACTMitochondrial toxicity has been implicated in the development of various toxicities, including hepatotoxicity. Therefore, mitochondrial toxicity has become a major screening factor in the early discovery phase of drug development. Several models have been developed to predict mitochondrial toxicity based on chemical structures. However, they only provide a binary classification of positive or negative results and do not provide the substructures that contribute to a positive decision. Therefore, we developed an artificial intelligence (AI) model to predict ...
Source: Journal of Toxicological Sciences - March 3, 2024 Category: Toxicology Authors: Yoshinobu Igarashi Ryosuke Kojima Shigeyuki Matsumoto Hiroaki Iwata Yasushi Okuno Hiroshi Yamada Source Type: research
Discovery and development of COVID-19 vaccines and therapeutics: nonclinical perspectives
J Toxicol Sci. 2024;49(3):79-94. doi: 10.2131/jts.49.79.ABSTRACTThe development and regulatory review of BNT162b2, a COVID-19 vaccine, and PaxlovidTM (nirmatrelvir tablets/ritonavir tablets), a COVID-19 therapeutic, are benchmarks for accelerated innovation during a global pandemic. Rapid choice of the SARS-CoV-2 spike protein and main protease (Mpro) as targets for the vaccine and therapeutic, respectively, leveraged the available knowledge of the biology of SARS-CoV-2 and related viruses. The nonclinical immunogenicity and safety of BNT162b2 was rigorously assessed. Likewise, a comprehensive nonclinical safety assessment...
Source: Journal of Toxicological Sciences - March 3, 2024 Category: Toxicology Authors: Nasir Khan Jean Sathish Cynthia M Rohde Source Type: research
Possible nonimmunological toxicological mechanisms of vesnarinone-associated agranulocytosis in HL-60 cells: role of reduced glutathione as cytotoxic defense
In conclusion, we present the first demonstration of the cytotoxic effects and ROS production resulting from the MPO/H2O2/Cl- metabolic reaction of vesnarinone and newly identified the causative metabolite, M2, as the N-chloramine metabolite of M1, which induces cytotoxicity in HL-60 cells. Moreover, a protective role of GSH against the cytotoxicity was revealed. These findings suggest a possible nonimmunological cause of vesnarinone agranulocytosis.PMID:38432956 | DOI:10.2131/jts.49.95 (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - March 3, 2024 Category: Toxicology Authors: Toshihisa Koga Yuko Sahara Tadaaki Ohtani Kaneko Yosuke Ken Umehara Source Type: research
Drosophila melanogaster as potential alternative animal model for evaluating acute inhalation toxicity
In this study, we investigated the acute inhalation toxicity of methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT) in a D. melanogaster model. During exposure, environmental conditions, mass median aerodynamic and geometric standard diameters were measured. After inhalation exposure, the survival rate, climbing ability, and bang sensitivity were measured on days 1, 2, and 7. Notably, the survival rate of flies decreased in an exposure concentration-dependent manner. Climbing ability and bang sensitivity were also altered in the MIT/CMIT group, compared with the negative control group. Overall, these results...
Source: Journal of Toxicological Sciences - January 31, 2024 Category: Toxicology Authors: Yoon Cho Chul Min Park Yong-Ju Heo Hae-Bin Park Min-Seok Kim Source Type: research
Methylmercury-induced brain neuronal death in CHOP-knockout mice
In this study, to clarify whether CHOP mediates MeHg-induced apoptosis, we examined the effect of CHOP deletion on MeHg exposure in CHOP-knockout mice. Our data showed that CHOP deletion had no effect on MeHg exposure-induced weight loss or hindlimb impairment in mice, nor did it increase apoptosis or inhibit neuronal cell loss. Hence, CHOP plays little role in MeHg toxicity, and other apoptotic pathways coupled with ER stress may be involved in MeHg-induced cell death.PMID:38296529 | DOI:10.2131/jts.49.55 (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - January 31, 2024 Category: Toxicology Authors: Yuta Iijima Ryohei Miki Masatake Fujimura Seiichi Oyadomari Takashi Uehara Source Type: research
A simple air-liquid interface exposure system for exposing cultured human 3D epidermis and cornea to PM2.5 collected through cyclonic separation
In this study, we developed an air-liquid interface exposure system for exposing cultured human 3D epidermis and cornea to PM2.5 collected through cyclonic separation. PM2.5 suspension was nebulized in an acrylic chamber, and the resulting mist was pumped through a diffusion dryer into a glass exposure chamber. A particle counter was connected to the exposure chamber to continuously measure the spatial mass concentration of PM. Human 3D epidermis was cultured in the exposure chamber. Exposure of the human 3D epidermis to PM aerosol increased interleukin-8 release into the media around 50 µg/m3. Mass concentrations above 1...
Source: Journal of Toxicological Sciences - January 31, 2024 Category: Toxicology Authors: Maori Kono Masayuki Takaishi Tomoaki Okuda Masashi Fujihara Seisuke Noguchi Yasuhiro Ishihara Source Type: research
Valproic acid elevates HIF-1 α-mediated CGB expression and suppresses glucose uptake in BeWo cells
J Toxicol Sci. 2024;49(2):69-77. doi: 10.2131/jts.49.69.ABSTRACTPlacental dysfunction can disrupt pregnancy. However, few studies have assessed the effects of chemical-induced toxicity on placental function. Here, we examined the effects of valproic acid (VPA) as a model chemical on production of hormones and on glucose uptake in human choriocarcinoma cell line BeWo. Cells were treated with forskolin to differentiate into syncytiotrophoblasts, which were then treated with VPA for 72 hr. Real-time RT-PCR analysis showed that VPA significantly increased the mRNA expression of chorionic gonadotropin β (CGB), a hormone that i...
Source: Journal of Toxicological Sciences - January 31, 2024 Category: Toxicology Authors: Go Kitahara Kazuma Higashisaka Yurina Nakamoto Rena Yamamoto Wakako Okuno Momoe Serizawa Yuji Sakahashi Hirofumi Tsujino Yuya Haga Yasuo Tsutsumi Source Type: research
Drosophila melanogaster as potential alternative animal model for evaluating acute inhalation toxicity
In this study, we investigated the acute inhalation toxicity of methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT) in a D. melanogaster model. During exposure, environmental conditions, mass median aerodynamic and geometric standard diameters were measured. After inhalation exposure, the survival rate, climbing ability, and bang sensitivity were measured on days 1, 2, and 7. Notably, the survival rate of flies decreased in an exposure concentration-dependent manner. Climbing ability and bang sensitivity were also altered in the MIT/CMIT group, compared with the negative control group. Overall, these results...
Source: Journal of Toxicological Sciences - January 31, 2024 Category: Toxicology Authors: Yoon Cho Chul Min Park Yong-Ju Heo Hae-Bin Park Min-Seok Kim Source Type: research
Methylmercury-induced brain neuronal death in CHOP-knockout mice
In this study, to clarify whether CHOP mediates MeHg-induced apoptosis, we examined the effect of CHOP deletion on MeHg exposure in CHOP-knockout mice. Our data showed that CHOP deletion had no effect on MeHg exposure-induced weight loss or hindlimb impairment in mice, nor did it increase apoptosis or inhibit neuronal cell loss. Hence, CHOP plays little role in MeHg toxicity, and other apoptotic pathways coupled with ER stress may be involved in MeHg-induced cell death.PMID:38296529 | DOI:10.2131/jts.49.55 (Source: Journal of Toxicological Sciences)
Source: Journal of Toxicological Sciences - January 31, 2024 Category: Toxicology Authors: Yuta Iijima Ryohei Miki Masatake Fujimura Seiichi Oyadomari Takashi Uehara Source Type: research
A simple air-liquid interface exposure system for exposing cultured human 3D epidermis and cornea to PM2.5 collected through cyclonic separation
In this study, we developed an air-liquid interface exposure system for exposing cultured human 3D epidermis and cornea to PM2.5 collected through cyclonic separation. PM2.5 suspension was nebulized in an acrylic chamber, and the resulting mist was pumped through a diffusion dryer into a glass exposure chamber. A particle counter was connected to the exposure chamber to continuously measure the spatial mass concentration of PM. Human 3D epidermis was cultured in the exposure chamber. Exposure of the human 3D epidermis to PM aerosol increased interleukin-8 release into the media around 50 µg/m3. Mass concentrations above 1...
Source: Journal of Toxicological Sciences - January 31, 2024 Category: Toxicology Authors: Maori Kono Masayuki Takaishi Tomoaki Okuda Masashi Fujihara Seisuke Noguchi Yasuhiro Ishihara Source Type: research
