 Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
| A B C D E F G H I J K L M N O P Q R S T U V W X Y Z | | The end of the list has been reached or no journals were found for your choice. |
|
|
- Cross-species applicability of an adverse outcome pathway network for
thyroid hormone system disruption-
Free pre-print version: Loading...
Rate this result:
What is this?
Please help us test our new pre-print finding feature by giving the pre-print link a rating.
A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Pages: 1 - 27
Abstract: AbstractThyroid hormone system disrupting compounds are considered potential threats for human and environmental health. Multiple adverse outcome pathways (AOPs) for thyroid hormone system disruption (THSD) are being developed in different taxa. Combining these AOPs results in a cross-species AOP network for THSD which may provide an evidence-based foundation for extrapolating THSD data across vertebrate species and bridging the gap between human and environmental health. This review aimed to advance the description of the taxonomic domain of applicability (tDOA) in the network to improve its utility for cross-species extrapolation. We focused on the molecular initiating events (MIEs) and adverse outcomes (AOs) and evaluated both their plausible domain of applicability (taxa they are likely applicable to) and empirical domain of applicability (where evidence for applicability to various taxa exists) in a THSD context. The evaluation showed that all MIEs in the AOP network are applicable to mammals. With some exceptions, there was evidence of structural conservation across vertebrate taxa and especially for fish and amphibians, and to a lesser extent for birds, empirical evidence was found. Current evidence supports the applicability of impaired neurodevelopment, neurosensory development (eg, vision) and reproduction across vertebrate taxa. The results of this tDOA evaluation are summarized in a conceptual AOP network that helps prioritize (parts of) AOPs for a more detailed evaluation. In conclusion, this review advances the tDOA description of an existing THSD AOP network and serves as a catalog summarizing plausible and empirical evidence on which future cross-species AOP development and tDOA assessment could build.
PubDate: Wed, 05 Jul 2023 00:00:00 GMT
DOI: 10.1093/toxsci/kfad063
Issue No: Vol. 195, No. 1 (2023)
- Role of Nrf2 in 1,2-dichloropropane-induced cell proliferation and DNA
damage in the mouse liver-
Free pre-print version: Loading...
Rate this result:
What is this?
Please help us test our new pre-print finding feature by giving the pre-print link a rating.
A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Pages: 28 - 41
Abstract: Abstract1,2-Dichloropropane (1,2-DCP) is recognized as the causative chemical of occupational cholangiocarcinoma in printing workers in Japan. However, the cellular and molecular mechanisms of 1,2-DCP-induced carcinogenesis remains elusive. The present study investigated cellular proliferation, DNA damage, apoptosis, and expression of antioxidant and proinflammatory genes in the liver of mice exposed daily to 1,2-DCP for 5 weeks, and the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in these responses. Wild-type and Nrf2-knockout (Nrf2−/−) mice were administered 1,2-DCP by gastric gavage, and then the livers were collected for analysis. Immunohistochemistry for BrdU or Ki67 and TUNEL assay revealed that exposure to 1,2-DCP dose-dependently increased proliferative cholangiocytes, whereas decreased apoptotic cholangiocytes in wild-type mice but not in Nrf2−/− mice. Western blot and quantitative real-time PCR showed that exposure to 1,2-DCP increased the levels of DNA double-strand break marker γ-H2AX and mRNA expression levels of NQO1, xCT, GSTM1, and G6PD in the livers of wild-type mice in a dose-dependent manner, but no such changes were noted in Nrf2−/− mice. 1,2-DCP increased glutathione levels in the liver of both the wild-type and Nrf2−/− mice, suggesting that an Nrf2-independent mechanism contributes to 1,2-DCP-induced increase in glutathione level. In conclusion, the study demonstrated that exposure to 1,2-DCP induced proliferation but reduced apoptosis in cholangiocytes, and induced double-strand DNA breaks and upregulation of antioxidant genes in the liver in an Nrf2-dependent manner. The study suggests a role of Nrf2 in 1,2-DCP-induced cell proliferation, antiapoptotic effect, and DNA damage, which are recognized as key characteristics of carcinogens.
PubDate: Fri, 16 Jun 2023 00:00:00 GMT
DOI: 10.1093/toxsci/kfad059
Issue No: Vol. 195, No. 1 (2023)
- Human-relevant exposure to di-n-butyl phthalate tampers with the ovarian
insulin-like growth factor 1 system and disrupts folliculogenesis in young
adult mice-
Free pre-print version: Loading...
Rate this result:
What is this?
Please help us test our new pre-print finding feature by giving the pre-print link a rating.
A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Pages: 42 - 52
Abstract: AbstractPhthalates are compounds used in consumer and medical products worldwide. Phthalate exposure in women has been demonstrated by detection of phthalate metabolites in their urine and ovarian follicular fluid. High urinary phthalate burden has been associated with reduced ovarian reserve and oocyte retrieval in women undergoing assisted reproduction. Unfortunately, no mechanistic explanation for these associations is available. In short term in vivo and in vitro animal studies modeling human-relevant exposures to di-n-butyl phthalate (DBP), we have identified ovarian folliculogenesis as a target for phthalate exposures. In the present study, we investigated whether DBP exposure negatively influences insulin-like growth factor 1 (IGF1) signaling in the ovary and disrupts ovarian folliculogenesis. CD-1 female mice were exposed to corn oil (vehicle) or DBP (10 µg/kg/day, 100 µg/kg/day, or 1000 mg/kg/day) for 20–32 days. Ovaries were collected as animals reached the proestrus stage to achieve estrous cycle synchronization. Levels of mRNAs encoding IGF1 and 2 (Igf1 and Igf2), IGF1 receptor (Igf1r), and IGF-binding proteins 1–6 (Ifgbp1–6) were measured in whole ovary homogenates. Ovarian follicle counts and immunostaining for phosphorylated IGF1R protein (pIGF1R) were used to evaluate folliculogenesis and IGF1R activation, respectively. DBP exposure, at a realistic dose that some women may experience (100 µg/kg/day for 20–32 days), reduced ovarian Igf1 and Igf1r mRNA expression and reduced small ovarian follicle numbers and primary follicle pIGF1R positivity in DBP-treated mice. These findings reveal that DBP tampers with the ovarian IGF1 system and provide molecular insight into how phthalates could influence the ovarian reserve in females.
PubDate: Thu, 13 Jul 2023 00:00:00 GMT
DOI: 10.1093/toxsci/kfad064
Issue No: Vol. 195, No. 1 (2023)
- Prenatal exposure to diethylstilbestrol has long-lasting,
transgenerational impacts on fertility and reproductive development-
Free pre-print version: Loading...
Rate this result:
What is this?
Please help us test our new pre-print finding feature by giving the pre-print link a rating.
A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Pages: 53 - 60
Abstract: AbstractSignificant decreases in fertility have been observed over the past 50 years, with female conception rates dropping by 44% and male sperm counts decreasing by over 50%. This dramatic decrease in fertility can be attributed in part to our increasing exposure to endocrine disrupting chemicals (EDCs). Diethylstilbestrol (DES) is an estrogenic EDC that was prescribed to millions of pregnant women between 1940 and 1970 and resulted in detrimental reproductive effects in the offspring that were exposed in utero. Women who were exposed to DES in utero experienced higher rates of infertility, pregnancy complications, and reproductive cancers. Alarmingly, there is evidence to suggest that these effects may persist in the grandchildren and great grandchildren of exposed women. To define the transgenerational reproductive impacts in females following exposure to DES, gestating mice were exposed to DES and the effects monitored in the female descendants across 3 generations. There was a trend for reduced pregnancy rate and fertility index seen across the generations and moreover, the anogenital distance (AGD) was significantly reduced up until the third, unexposed generation. The onset of puberty was also significantly affected, with the timing of vaginal opening occurring significantly earlier in DES descendants. These results indicate a transgenerational effect of DES on multiple reproductive parameters including fertility, timing of puberty, and AGD. These data have significant implications for more than 50 million DES descendants worldwide as well as raising concerns for the ongoing health impacts caused by exposures to other estrogenic EDCs which are pervasive in our environment.
PubDate: Thu, 20 Jul 2023 00:00:00 GMT
DOI: 10.1093/toxsci/kfad066
Issue No: Vol. 195, No. 1 (2023)
- CardioMotion: identification of functional and structural cardiotoxic
liabilities in small molecules through brightfield kinetic imaging-
Free pre-print version: Loading...
Rate this result:
What is this?
Please help us test our new pre-print finding feature by giving the pre-print link a rating.
A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Pages: 61 - 70
Abstract: AbstractCardiovascular toxicity is an important cause of drug failures in the later stages of drug development, early clinical safety assessment, and even postmarket withdrawals. Early-stage in vitro assessment of potential cardiovascular liabilities in the pharmaceutical industry involves assessment of interactions with cardiac ion channels, as well as induced pluripotent stem cell-derived cardiomyocyte-based functional assays, such as calcium flux and multielectrode-array assays. These methods are appropriate for the identification of acute functional cardiotoxicity but structural cardiotoxicity, which manifests effects after chronic exposure, is often only captured in vivo. CardioMotion is a novel, label-free, high throughput, in vitro assay and analysis pipeline which records and assesses the spontaneous beating of cardiomyocytes and identifies compounds which impact beating. This is achieved through the acquisition of brightfield images at a high framerate, combined with an optical flow-based python analysis pipeline which transforms the images into waveform data which are then parameterized. Validation of this assay with a large dataset showed that cardioactive compounds with diverse known direct functional and structural mechanisms-of-action on cardiomyocytes are identified (sensitivity = 72.9%), importantly, known structural cardiotoxins also disrupt cardiomyocyte beating (sensitivity = 86%) in this method. Furthermore, the CardioMotion method presents a high specificity of 82.5%.
PubDate: Tue, 18 Jul 2023 00:00:00 GMT
DOI: 10.1093/toxsci/kfad065
Issue No: Vol. 195, No. 1 (2023)
- IL33-mediated NPM1 promotes fibroblast-to-myofibroblast transition via
ERK/AP-1 signaling in silica-induced pulmonary fibrosis-
Free pre-print version: Loading...
Rate this result:
What is this?
Please help us test our new pre-print finding feature by giving the pre-print link a rating.
A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Pages: 71 - 86
Abstract: AbstractSilicosis is a global occupational pulmonary disease due to the accumulation of silica dust in the lung. Lacking effective clinical drugs makes the treatment of this disease quite challenging in clinics largely because the pathogenic mechanisms remain obscure. Interleukin 33 (IL33), a pleiotropic cytokine, could promote wound healing and tissue repair via the receptor ST2. However, the mechanisms governing the involvement of IL33 in silicosis progression remain to be further explored. Here, we demonstrated that the IL33 levels in the lung sections were significantly overexpressed after bleomycin and silica treatment. Chromatin immunoprecipitation assay, knockdown, and reverse experiments were performed in lung fibroblasts to prove gene interaction following exogenous IL33 treatment or cocultured with silica-treated lung epithelial cells. Mechanistically, we illustrated that silica-stimulated lung epithelial cells secreted IL33 and further promoted the activation, proliferation, and migration of pulmonary fibroblasts by activating the ERK/AP-1/NPM1 signaling pathway in vitro. And more, treatment with NPM1 siRNA-loaded liposomes markedly protected mice from silica-induced pulmonary fibrosis in vivo. In conclusion, the involvement of NPM1 in the progression of silicosis is regulated by the IL33/ERK/AP-1 signaling axis, which is the potential therapeutic target candidate in developing novel antifibrotic strategies for pulmonary fibrosis.
PubDate: Mon, 03 Jul 2023 00:00:00 GMT
DOI: 10.1093/toxsci/kfad061
Issue No: Vol. 195, No. 1 (2023)
- CircRNA hsa_circ_0000043 acts as a miR-4492 sponge to promote lung cancer
progression via BDNF and STAT3 expression regulation in
anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide-transformed 16HBE
cells-
Free pre-print version: Loading...
Rate this result:
What is this?
Please help us test our new pre-print finding feature by giving the pre-print link a rating.
A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Pages: 87 - 102
Abstract: AbstractIncreasing evidence shows that circular RNA (circRNA) plays an important role in the progression of lung cancer. In this study, we found that has_circ_0000043 was highly expressed in 16HBE-T human bronchial epithelial cells that were malignantly transformed by benzo[a]pyrene-trans-7,8-diol-9,10-epoxide via circRNA microarray. We verified that hsa_circ_0000043 was also significantly overexpressed in lung cancer cell lines and tissues. Moreover, hsa_circ_0000043 overexpression was positively correlated with poor clinicopathological parameters, such as tumor-node metastasis stage, distant metastasis, lymph-node metastasis, and overall survival. In vitro assays revealed that hsa_circ_0000043 inhibition suppressed 16HBE-T cell proliferation, migration, and invasion. Furthermore, hsa_circ_0000043 inhibition suppressed tumor growth in a mouse xenograft model. We discovered that hsa_circ_0000043 binds with miR-4492, acting as a miR-4492 sponge. Decreased miR-4492 expression was also associated with poor clinicopathological parameters. Thus, hsa_circ_0000043 was shown to contribute to the proliferation, malignant transformation ability, migration, and invasion of 16HBE-T cells via miR-4492 sponging and BDNF and STAT3 involvement.
PubDate: Fri, 16 Jun 2023 00:00:00 GMT
DOI: 10.1093/toxsci/kfad060
Issue No: Vol. 195, No. 1 (2023)
- Machine learning reveals common transcriptomic signatures across rat brain
and placenta following developmental organophosphate ester exposure-
Free pre-print version: Loading...
Rate this result:
What is this?
Please help us test our new pre-print finding feature by giving the pre-print link a rating.
A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Pages: 103 - 122
Abstract: AbstractToxicogenomics is a critical area of inquiry for hazard identification and to identify both mechanisms of action and potential markers of exposure to toxic compounds. However, data generated by these experiments are highly dimensional and present challenges to standard statistical approaches, requiring strict correction for multiple comparisons. This stringency often fails to detect meaningful changes to low expression genes and/or eliminate genes with small but consistent changes particularly in tissues where slight changes in expression can have important functional differences, such as brain. Machine learning offers an alternative analytical approach for “omics” data that effectively sidesteps the challenges of analyzing highly dimensional data. Using 3 rat RNA transcriptome sets, we utilized an ensemble machine learning approach to predict developmental exposure to a mixture of organophosphate esters (OPEs) in brain (newborn cortex and day 10 hippocampus) and late gestation placenta of male and female rats, and identified genes that informed predictor performance. OPE exposure had sex specific effects on hippocampal transcriptome, and significantly impacted genes associated with mitochondrial transcriptional regulation and cation transport in females, including voltage-gated potassium and calcium channels and subunits. To establish if this holds for other tissues, RNAseq data from cortex and placenta, both previously published and analyzed via a more traditional pipeline, were reanalyzed with the ensemble machine learning methodology. Significant enrichment for pathways of oxidative phosphorylation and electron transport chain was found, suggesting a transcriptomic signature of OPE exposure impacting mitochondrial metabolism across tissue types and developmental epoch. Here we show how machine learning can complement more traditional analytical approaches to identify vulnerable “signature” pathways disrupted by chemical exposures and biomarkers of exposure.
PubDate: Mon, 03 Jul 2023 00:00:00 GMT
DOI: 10.1093/toxsci/kfad062
Issue No: Vol. 195, No. 1 (2023)
- Lead exposure suppresses the Wnt3a/β-catenin signaling to increase the
quiescence of hematopoietic stem cells via reducing the expression of CD70
on bone marrow-resident macrophages-
Free pre-print version: Loading...
Rate this result:
What is this?
Please help us test our new pre-print finding feature by giving the pre-print link a rating.
A 5 star rating indicates the linked pre-print has the exact same content as the published article.
Pages: 123 - 142
Abstract: AbstractLead (Pb) is a heavy metal highly toxic to human health in the environment. The aim of this study was to investigate the mechanism of Pb impact on the quiescence of hematopoietic stem cells (HSC). WT C57BL/6 (B6) mice treated with 1250 ppm Pb via drinking water for 8 weeks had increased the quiescence of HSC in the bone marrow (BM), which was caused by the suppressed activation of the Wnt3a/β-catenin signaling. Mechanically, a synergistic action of Pb and IFNγ on BM-resident macrophages (BM-Mφ) reduced their surface expression of CD70, which thereby dampened the Wnt3a/β-catenin signaling to suppress the proliferation of HSC in mice. In addition, a joint action of Pb and IFNγ also suppressed the expression of CD70 on human Mφ to impair the Wnt3a/β-catenin signaling and reduce the proliferation of human HSC purified from umbilical cord blood of healthy donors. Moreover, correlation analyses showed that the blood Pb concentration was or tended to be positively associated with the quiescence of HSC, and was or tended to be negatively associated with the activation of the Wnt3a/β-catenin signaling in HSC in human subjects occupationally exposed to Pb. Collectively, these data indicate that an occupationally relevant level of Pb exposure suppresses the Wnt3a/β-catenin signaling to increase the quiescence of HSC via reducing the expression of CD70 on BM-Mφ in both mice and humans.
PubDate: Wed, 12 Jul 2023 00:00:00 GMT
DOI: 10.1093/toxsci/kfad067
Issue No: Vol. 195, No. 1 (2023)
|
Hybrid journal (It can contain Open Access articles)
