Journal of Toxicological Sciences最新文献_第2页

Activation of the arylhydrocarbon receptor through maternal beta-naphthoflavone exposure in the neonatal kidney.

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.2131/jts.50.161

Wataru Yoshioka, Kanta Kikutake

{"title":"Activation of the arylhydrocarbon receptor through maternal beta-naphthoflavone exposure in the neonatal kidney.","authors":"Wataru Yoshioka, Kanta Kikutake","doi":"10.2131/jts.50.161","DOIUrl":"https://doi.org/10.2131/jts.50.161","url":null,"abstract":"The kidneys of neonates are vulnerable to stressors due to their immature structure and function. Excess activation of the transcription factor arylhydrocarbon receptor (AhR) in the kidneys of neonates can cause severe hydronephrosis, as shown previously using 2,3,7,8-tetrachlorodibenzo-p-dioxin, an AhR agonist. In this study, we aimed to clarify the conditions under which AhR activation leads to hydronephrosis using beta-naphthoflavone (BNF), another potent agonist of AhR. Mouse dams were fed a BNF-containing diet, and the kidneys of their pups were examined. Maternal BNF exposure on postnatal day 1 (PND 1) significantly activated AhR, as evidenced by the increased mRNA levels of the target genes. However, AhR activation was hardly detectable on PND 2 or subsequent days although the mice were continually fed the BNF-containing diet. Further, no hydronephrosis or a related alteration was observed. Similarly, maternal BNF exposure from PND 6 induced significant AhR activation on PND 6 but not on PND 14. The overproduction of prostaglandin E2 (PGE2), which is a pivotal mechanism in the development of neonatal hydronephrosis, was not observed, and no hydronephrosis was observed. These results suggested that the intense activation of AhR on PND 1 or 6 is insufficient to induce overproduction of PGE2 or hydronephrosis. Together with findings from previous studies, we conclude that the development of neonatal hydronephrosis depends on the duration and intensity of AhR activation.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 4","pages":"161-170"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Construction and evaluation of an open-source database for inhalation-based physiologically based kinetic modeling of selected categories for industrial chemicals.

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.2131/jts.50.57

Shigechika Yamamoto, Kikuo Yoshida, Mariko Matsumoto, Takashi Yamada

{"title":"Construction and evaluation of an open-source database for inhalation-based physiologically based kinetic modeling of selected categories for industrial chemicals.","authors":"Shigechika Yamamoto, Kikuo Yoshida, Mariko Matsumoto, Takashi Yamada","doi":"10.2131/jts.50.57","DOIUrl":"https://doi.org/10.2131/jts.50.57","url":null,"abstract":"A physiologically based kinetic (PBK) model is used for predicting chemical concentrations of toxicological concern in target tissues. Such models are important for understanding toxicokinetics. However, it is challenging to obtain chemical-specific empirical parameter values used for PBK modeling. Thus, developing methods predicting these values is necessary. Herein, we researched PBK models of inhalation exposure to industrial chemicals and developed a database of parameters of approximately 200 chemicals in humans and rodents. Next, the chemicals in the database were classified into three categories (I, IIA, and IIB) based on the intermolecular interactions for humans and rats. Quantitative relationships between blood/air and tissue/blood partition coefficients and physicochemical parameters were derived for the chemicals in each category. Regression analyses of blood/air and fat/blood partition coefficients against Henry's law constant and log D at pH 7.4 for chemicals in category IIA for humans, in which van der Waals and dipole-dipole interactions were involved, yielded 0.88 and 0.54 coefficients of determination, respectively. Moreover, these methods worked for other categories and species. The metabolic parameters maximal velocity (Vmax) and Michaelis-Menten constant (Km) of the chemicals that are primarily metabolized by cytochrome P450 were calculated for humans and rats. Multiple regression analyses of logs Vmax and Km against the occurrence frequency of molecular fragments showed good correlations, respectively. The aforementioned models predicted values close to the reported values for test chemicals within the applicability domains. Our approach could also be applied to other chemicals within the domains that are not included in the database.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 2","pages":"57-68"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prolyl hydroxylase domain enzymes (isoforms 1-3, PHD1-3), but not factor-inhibiting HIF-1 (FIH-1), interact with the IKK complex and attenuate LPS-activated NF-kappa-B.

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.2131/jts.50.105

Akiyoshi Tamura, Koji Kitayama, Mutsumi Adachi, Kentaro Hashimoto, Ami Oguro, Susumu Imaoka

{"title":"Prolyl hydroxylase domain enzymes (isoforms 1-3, PHD1-3), but not factor-inhibiting HIF-1 (FIH-1), interact with the IKK complex and attenuate LPS-activated NF-kappa-B.","authors":"Akiyoshi Tamura, Koji Kitayama, Mutsumi Adachi, Kentaro Hashimoto, Ami Oguro, Susumu Imaoka","doi":"10.2131/jts.50.105","DOIUrl":"https://doi.org/10.2131/jts.50.105","url":null,"abstract":"Hypoxia induces the expression of nuclear factor kappa B (NF-kappa-B). NF-kappa-B functions by forming dimers from five main subunits: p65 (RelA), RelB, p52, p50, and c-Rel. In the classical pathway, NF-kappa-B activity is regulated by the degradation-inducing factor I kappa B kinase (IKK). IKK is composed of an α/β isomer and essential modulator NEMO (γ) subunits in the classical pathway, which may be the major pathway for NF-kappa-B signaling. In the present study, we focused on factor-inhibiting HIF-1 (FIH-1) and Prolyl hydroxylase domain enzyme (PHD), which have been identified as oxygen concentration-dependent regulators of HIF-1α. PHD has three isoforms: PHD1, PHD2, and PHD3, which have different affinities towards HIF-1α. We examined the interactions between IKKα/β and PHD1-3 by immunoprecipitation. PHDs efficiently interacted with IKKα/β. Furthermore, the overexpression of PHDs decreased the mRNA level of IL-1β, a downstream factor of NF-kappa-B activated by LPS. The overexpression of PHD1 and PHD2 markedly reduced IKKα/β protein levels; however, the effects of PHD3 were weaker than those of PHD1 and PHD2. Mutants of the active sites of PHD1 and PHD2 did not decrease IKKα/β protein levels, and a mutation in the active site of PHD3 did not affect IKKα/β protein levels. We also attempted to investigate the interactions of FIH-1 with IKKα/β and IκBα by immunoprecipitation, but found none. Moreover, IKKα/β and p65 protein levels were not affected by the overexpression of FIH-1. Collectively, these results suggest that PHDs directly regulated IKK protein levels, while FIH-1 did not affect the NF-kappa-B classical pathway.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 3","pages":"105-116"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Effect of the barrier function of stratum corneum and viable epidermis and dermis on the skin concentration of topically applied chemicals.

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.2131/jts.50.187

Hiroaki Todo, Takeshi Oshizaka, Syuuhei Komatsu, Kenji Sugibayashi

{"title":"Effect of the barrier function of stratum corneum and viable epidermis and dermis on the skin concentration of topically applied chemicals.","authors":"Hiroaki Todo, Takeshi Oshizaka, Syuuhei Komatsu, Kenji Sugibayashi","doi":"10.2131/jts.50.187","DOIUrl":"https://doi.org/10.2131/jts.50.187","url":null,"abstract":"Three-dimensional cultured skin (3D skin) models have been utilized for in vitro skin permeation tests to evaluate the skin permeation rate and local effects (efficacy and toxicity) of applied chemicals, particularly from the perspective of the 3Rs (reduction, replacement, refinement) approach. The steady-state concentration of applied chemicals at different depths in the viable epidermis and dermis (VED) is affected by their skin permeation parameters, such as permeability coefficient (Kp) and partition coefficient (K) from the donor solution to the skin of the chemicals. In the present study, the steady-state concentration of chemicals in the VED of EpiDerm 606X (EpiDerm) as representative of a 3D skin model were compared with hairless rat skin. The VED concentrations of chemicals in EpiDerm were higher than those in hairless rat skin when a model hydrophilic compound, antipyrine, and a model lipophilic compound, flurbiprofen, were applied, suggesting that the barrier functions of the VED against the whole skin were higher in EpiDerm than in hairless rat skin. When an ester compound, ethyl nicotinate, was applied, the VED concentration of nicotinic acid, a metabolite of ethyl nicotinate, was lower in EpiDerm than in hairless rat skin. These differences in the VED concentrations of applied chemicals might be related to false-positives and -negatives of topical effects evaluated with 3D skin models. It is important to pay particular attention to differences in VED concentration in 3D skin models and real skin when evaluating local efficacy and toxicity using 3D skin models.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 4","pages":"187-198"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Determination of putrefactive amine and ammonia concentrations around decomposed corpses.

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.2131/jts.50.75

Hiroaki Sato, Takahiro Umehara, Satoshi Kimura, Toshiko Tanaka, Sang-Eun Kim

{"title":"Determination of putrefactive amine and ammonia concentrations around decomposed corpses.","authors":"Hiroaki Sato, Takahiro Umehara, Satoshi Kimura, Toshiko Tanaka, Sang-Eun Kim","doi":"10.2131/jts.50.75","DOIUrl":"https://doi.org/10.2131/jts.50.75","url":null,"abstract":"The surface of a rotting corpse is covered with liquid decomposition products that have flowed out of the body that include putrefactive amines produced via putrefaction and decarboxylation reactions of proteins. Ammonia generated by deamination is also present around the corpse as a liquid or gas. As these putrefactive substances are toxic to humans, we attempted to measure the concentration of putrefactive substances in decomposed corpses in this study. Liquid putrefaction products were collected from the surface of a corpse, and the concentrations of putrefactive amines such as histamine, tyramine, phenethylamine, and tryptamine were analyzed by LC-MS/MS. Ammonia in the liquid and air around the corpse was also measured. Putrefactive amines and ammonia were present on all corpse surfaces. The highest concentrations and postmortem days in parentheses were as follows: histamine 2.26 mg/g (15 days), tyramine 1.77 mg/g (16 days), phenethylamine 4.90 mg/g (24 days), tryptamine 1.58 mg/g (17 days) and ammonia 25.6 mg/g (24 days postmortem). The highest concentration of ammonia in the air was 1310 ppm at 24 days postmortem. The ammonia level in the air around a corpse is toxic to humans. Inhalation of putrefactive amines and ammonia can cause chemical irritation to the respiratory tract and the skin and damage the mucous membrane of the eye. Oral ingestion can also cause poisoning symptoms such as blood pressure changes and headaches. Adequate protection against putrefactive substances is required when in contact with decaying corpses.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 2","pages":"75-81"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Perfluorooctane sulfonate induces hepatotoxicity through promoting inflammation, cell death and autophagy in a rat model.

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.2131/jts.50.45

Leilei Tang, Jianjun Zhu, Sheng Zhuge, Jiawen Yu, Guojun Jiang

{"title":"Perfluorooctane sulfonate induces hepatotoxicity through promoting inflammation, cell death and autophagy in a rat model.","authors":"Leilei Tang, Jianjun Zhu, Sheng Zhuge, Jiawen Yu, Guojun Jiang","doi":"10.2131/jts.50.45","DOIUrl":"https://doi.org/10.2131/jts.50.45","url":null,"abstract":"Perfluorooctane sulfonate (PFOS) is reported to cause hepatotoxicity in animals and humans. However, the underlying mechanism by which it affects organelle toxicity in the liver are not well elucidated yet. This study aimed to investigate the mechanisms underlying PFOS-induced hepatic toxicity, focusing on inflammation, cell death, and autophagy. We established a PFOS-exposed Sprague-Dawley (SD) rat liver injury model by intraperitoneal injection of PFOS (1 mg/kg and 10 mg/kg body weight) every alternate day for 15 days. Our findings indicated that PFOS increased liver weight, caused lipid disorder and hepatic steatosis in rats. Meanwhile, PFOS disrupted the structure of mitochondria, increased accumulation of reactive oxygen species (ROS), repressed superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) levels, and elevated malondialdehyde (MDA) and nitric oxide synthase (NOS) amounts. We found PFOS induced inflammation as evidenced by activation of NOD-like receptor protein 3 (NLRP3), Cleaved cysteine-aspartic acid protease (caspase)1, tumor necrosis factor (TNF)α and interleukin (IL)-1β levels. Moreover, PFOS exposure significantly decreased B-cell lymphoma2 (Bcl2)/Bcl2 associated X (Bax) ratio and increased the protein expression of Cleaved caspase-3. Compared with the control group, PFOS upregulated the protein expression of necroptotic markers and autophagy-related proteins. In conclusion, PFOS induced inflammation, cell death, and autophagy through oxidative stress by ROS overload, thereby providing a mechanistic explanation for PFOS-induced hepatotoxicity.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 2","pages":"45-55"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Potential of connexin 32 as a predictive marker for drug-induced cholestatic liver injury in a collagen vitrigel-culture model of HepG2-NIAS cells, a new subline of HepG2 cells, with bile canaliculus-like structures.

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.2131/jts.50.135

Miaki Uzu, Toshiaki Takezawa

{"title":"Potential of connexin 32 as a predictive marker for drug-induced cholestatic liver injury in a collagen vitrigel-culture model of HepG2-NIAS cells, a new subline of HepG2 cells, with bile canaliculus-like structures.","authors":"Miaki Uzu, Toshiaki Takezawa","doi":"10.2131/jts.50.135","DOIUrl":"https://doi.org/10.2131/jts.50.135","url":null,"abstract":"Cholestatic drug-induced liver injury (DILI) is caused by the aberrant excretion of bile acids (BAs) from hepatocytes via bile canaliculus-like structures (BCLSs) into the bile ducts. The precise in vitro evaluation method for cholestatic DILI has not been established due to a lack of specific markers and cell resources. We previously reported that HepG2-NIAS cells cultured on a collagen vitrigel (CV) membrane formed BCLSs with high protein expression of transporters involved in the excretion of BAs, including bile salt export pump (BSEP). In this study, the potential of connexin (Cx) 32, a component of gap junction, as a predictive marker for cholestatic DILI was investigated using a CV-culture model of HepG2-NIAS cells. The cells were treated with 7 drugs with different DILI-risk levels, and cell toxicity and Cx32 expression were evaluated. Cell toxicity was significantly increased not only by high DILI-risk drugs (troglitazone and cyclosporine A) but also by chlorpromazine with low DILI-risk. Furthermore, cell toxicity of troglitazone was not enhanced by a co-treatment with taurocholate, suggesting the low involvement of inhibition of BA excretion via BSEP in cholestatic DILI. In contrast, the total protein expression of Cx32 and co-localization of Cx32 and F-actin, which is composed of BCLSs, were significantly increased only by high DILI-risk drugs. Treatment with high DILI-risk drugs also induced the increased protein expression of zonula occludens (ZO)-1, which supports BCLSs concerted with Cx32. These results suggest that Cx32 expression in the CV-culture model of HepG2-NIAS cells may be a prominent predictive marker for cholestatic DILI.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 3","pages":"135-145"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In silico model to predict dermal absorption of chemicals in finite dose conditions.

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.2131/jts.50.171

Ibuki Narita, Hiroaki Todo, Chihiro Fujiwara, Hiroyuki Teramae, Takeshi Oshizaka, Shoko Itakura, Syuuhei Komatsu, Kozo Takayama, Kenji Sugibayashi

{"title":"In silico model to predict dermal absorption of chemicals in finite dose conditions.","authors":"Ibuki Narita, Hiroaki Todo, Chihiro Fujiwara, Hiroyuki Teramae, Takeshi Oshizaka, Shoko Itakura, Syuuhei Komatsu, Kozo Takayama, Kenji Sugibayashi","doi":"10.2131/jts.50.171","DOIUrl":"https://doi.org/10.2131/jts.50.171","url":null,"abstract":"The development of in silico approaches that can estimate the dermal absorption of chemicals exposed in practical conditions is highly anticipated. In the present study, an in silico model to estimate both the dermal absorption rate and dermal permeation profile was developed for the application of chemicals in finite dose conditions. Forty-three chemicals with molecular weights in the range 116-362 and logKo/w in the range 1.1-4.5 were used to develop an in silico model. A gradient boosting tree approach was applied to estimate permeation parameters for diffusion and partition coefficients of the chemicals in skin using physicochemical parameters of the chemicals such as molecular weight, lipophilicity, and the highest and lowest occupied molecular orbitals as the descriptor. In addition, 11 chemicals with different molecular weights and lipophilicities were applied on excised human skin in a finite dose condition, and dermal absorption profiles were obtained. Consideration of donor-solvent evaporation time, saturated concentrations of the chemicals, and donor-solvent coverage area on the skin surface, in addition to estimated skin permeation parameters of the chemicals, showed comparatively good dermal absorption profiles, although some cases of underestimation of dermal absorption were identified. It will be necessary to verify the accuracy of this model through experiments using more chemicals. However, the obtained results suggested that the established model may be valid to estimate the dermal absorption of chemicals in practical conditions.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 4","pages":"171-186"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-term exposure to urban particulate matter exacerbates mortality after ischemic stroke in mice.

IF 1.8 4区医学

Journal of Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.2131/jts.50.147

Nami Ishihara, Miki Tanaka, Kaede Namba, Shinji Kawano, Sakuno Nishimura, Naoyuki Nezu, Tatsuto Nakane, Ami Oguro, Tomoaki Okuda, Kouichi Itoh, Yu Nabetani, Yasuhiro Ishihara

{"title":"Long-term exposure to urban particulate matter exacerbates mortality after ischemic stroke in mice.","authors":"Nami Ishihara, Miki Tanaka, Kaede Namba, Shinji Kawano, Sakuno Nishimura, Naoyuki Nezu, Tatsuto Nakane, Ami Oguro, Tomoaki Okuda, Kouichi Itoh, Yu Nabetani, Yasuhiro Ishihara","doi":"10.2131/jts.50.147","DOIUrl":"https://doi.org/10.2131/jts.50.147","url":null,"abstract":"Exposure to fine particulate matter (PM2.5) has been epidemiologically reported to worsen the prognosis of ischemic stroke; however, the details have not been investigated. One of the major toxic mechanisms of PM2.5 inhalation is oxidative stress, which is mediated by reactive oxygen species generated by PM2.5 components such as metals and polycyclic aromatic hydrocarbons. In this study, we examined the effects of long-term exposure to urban particulate matter, focusing on oxidative stress, on prognosis after ischemic stroke in mice. When mice were intranasally exposed for 28 days to an urban aerosol collected in Beijing, China (CRM28), microglial activation was observed in the cerebral cortex, indicating that CRM28 induced neuroinflammation. CRM28 exposure resulted in increased serum levels of brain natriuretic peptide and troponin I, suggesting that cardiac injury was elicited by CRM28. Lung inflammation was also observed following CRM28 exposure; however, systemic inflammation was not detected. Mice exposed to CRM28 showed an exacerbation of mortality after ischemic stroke induction compared with vehicle mice. A vitamin E-rich diet suppressed CRM28-induced lipid peroxidation in the heart and lungs but not in the brain. A vitamin E-rich diet also attenuated cardiac injury and lung inflammation induced by CRM28 exposure, whereas neuroinflammation was not affected. Mortality after ischemic stroke improved with the administration of a vitamin E-rich diet. Considering that systemic inflammation did not occur, cardiac injury induced by oxidative stress under exposure to urban particulate matter may be involved in increased mortality after ischemic stroke. Antioxidation under air pollution is fundamental for protection against ischemic stroke.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"50 3","pages":"147-159"},"PeriodicalIF":1.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery and development of COVID-19 vaccines and therapeutics: nonclinical perspectives. COVID-19 疫苗和疗法的发现与开发：非临床视角。

IF 2 4区医学

Journal of Toxicological Sciences Pub Date : 2024-01-01 DOI: 10.2131/jts.49.79

Nasir Khan, Jean Sathish, Cynthia M Rohde

{"title":"Discovery and development of COVID-19 vaccines and therapeutics: nonclinical perspectives.","authors":"Nasir Khan, Jean Sathish, Cynthia M Rohde","doi":"10.2131/jts.49.79","DOIUrl":"10.2131/jts.49.79","url":null,"abstract":"The 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 was conducted for the therapeutic candidates, lufotrelvir (PF-07304814) and nirmatrelvir (PF-07321332). The development and regulatory review of BNT162b2 and Paxlovid was enabled through close collaboration of the pharmaceutical industry with regulatory agencies and public health organizations. This experience highlights approaches that could be adopted for pandemic preparedness including risk-based investment strategies, conduct of activities in parallel that normally are conducted sequentially, quick kill decisions, simultaneous evaluation of multiple candidates, and use of flexible, established vaccine platforms.","PeriodicalId":17654,"journal":{"name":"Journal of Toxicological Sciences","volume":"49 3","pages":"79-94"},"PeriodicalIF":2.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140022108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0