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Downregulation of Rad51 participates in OTA-induced DNA double-strand breaks in GES-1 cells in vitro.
Abstract Ochratoxin A (OTA), a mycotoxin produced by ubiquitous Aspergilli, is carcinogenic, teratogenic, and nephrotoxic in both humans and animals. Our previous study found that OTA induced DNA double-strand breaks (DSBs) and resulted in G2 phase arrest in human gastric epithelium immortalized (GES-1) cells. DSBs can cause genomic instability, mutations, and neoplastic transformations, and improper repair of DSBs may lead to the development of cancer. Rad51 is a key protein in the homologous recombination (HR) pathway of DSBs repair. The roles of Rad51 in the repair of DNA damage vary in response to different ty...
Source: Toxicology Letters - February 10, 2014 Category: Toxicology Authors: Lian H, Cui J, Wang Y, Liu J, Wang J, Shen H, Xing L, Wang J, Yan X, Zhang X Tags: Toxicol Lett Source Type: research

Long-term arsenite exposure induces premature senescence in B cell lymphoma A20 cells.
In this study, we further investigated the consequences of long-term arsenite exposure of A20 cells. The results demonstrated that exposure to 10 μM sodium arsenite up to 14 days induces a great increase in G0/G1 arrest, irreversible cell growth suppression, cellular morphological changes and positive staining for senescence-associated β-galactosidase. The long-term arsenite exposure also induced up-regulation of p16(INK4a) followed by robust accumulation of p130 and activation of the p53 pathway. Knockdown experiments with siRNA showed that p130 accumulation is essential for cell cycle arrest by long-term arsenite exp...
Source: Archives of Toxicology - March 19, 2015 Category: Toxicology Authors: Okamura K, Nohara K Tags: Arch Toxicol Source Type: research

Bifunctional Alkylating Agent-Mediated MGMT-DNA Cross-linking and its Proteolytic Cleavage in 16HBE Cells.
Abstract Nitrogen mustard (NM), a bifunctional alkylating agent (BAA), contains two alkyl arms and can act as a cross-linking bridge between DNA and protein to form a DNA-protein cross-link (DPC). O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme for alkyl adducts removal, is found to enhance cell sensitivity to BAAs and to promote damage, possibly due to its stable covalent cross-linking with DNA mediated by BAAs. To investigate MGMT-DNA cross-link (mDPC) formation and its possible dual roles in NM exposure, human bronchial epithelial cell line 16HBE was subjected to different concentrations of...
Source: Toxicology and Applied Pharmacology - June 20, 2016 Category: Toxicology Authors: Cheng J, Ye F, Dan G, Zhao Y, Wang B, Zhao J, Sai Y, Zou Z Tags: Toxicol Appl Pharmacol Source Type: research

Yangonin protects against cholestasis and hepatotoxity via activation of farnesoid X receptor in vivo and in vitro.
Abstract Cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a newly therapeutic strategy against cholestasis. The purpose of the current study is to screen novel FXR agonists and verify the anti-cholestasis effect of yangonin in vivo and in vitro. The computational strategy of two-dimensional virtual screening was used to search for new FXR agonists, and dual-luci...
Source: Toxicology and Applied Pharmacology - April 13, 2018 Category: Toxicology Authors: Gao X, Fu T, Wang C, Ning C, Liu K, Liu Z, Sun H, Ma X, Huo X, Yang X, Zou M, Meng Q Tags: Toxicol Appl Pharmacol Source Type: research

Crystalline silica alters Sulfatase-1 expression in rat lungs which influences hyper-proliferative and fibrogenic effects in human lung epithelial cells.
In this study, CS-induced down-regulation of SULF1, and increases in Sulfated-HSPGs, were determined in human BECs, and in rat lungs. By siRNA and plasmid transfection techniques the effects of SULF1 expression on silica-induced fibrogenic and proliferative gene expression were determined. These studies confirmed down-regulation of SULF1 and subsequent increases in sulfated-HSPGs in vitro. Moreover, short-term exposure of rats to CS resulted in similar changes in vivo. Conversely, effects were reversed after long term CS exposure of rats. SULF1 knockdown, and overexpression alleviated and exacerbated silica-induced decreas...
Source: Toxicology and Applied Pharmacology - April 16, 2018 Category: Toxicology Authors: Perkins TN, Peeters PM, Albrecht C, Schins RPF, Dentener MA, Mossman BT, Wouters EFM, Reynaert NL Tags: Toxicol Appl Pharmacol Source Type: research

Nephrotoxicity instead of immunotoxicity of OTA is induced through DNMT1-dependent activation of JAK2/STAT3 signaling pathway by targeting SOCS3.
Abstract Ochratoxin A (OTA) is reported to induce nephrotoxicity and immunotoxicity in animals and humans. However, the underlying mechanism and the effects of OTA on DNA damage have not been reported until now. The present study aims to investigate OTA-induced cytotoxicity and DNA damage and the underlying mechanism in PK15 cells and PAMs. The results showed that OTA at 2.0-8.0 µg/mL for 24 h induced cytotoxicity and DNA damage in PK15 cells and PAMs as demonstrated by decreasing cell viabilities and mRNA levels of DNA repair genes (OGG1, NEIL1 and NEIL3), increasing LDH release, Annexin V staining cells, apop...
Source: Archives of Toxicology - March 27, 2019 Category: Toxicology Authors: Gan F, Zhou X, Zhou Y, Hou L, Chen X, Pan C, Huang K Tags: Arch Toxicol Source Type: research

High mobility group box-1 protects against Aflatoxin G1-induced pulmonary epithelial cell damage in the lung inflammatory environment.
Abstract Aflatoxin G1 (AFG1) is a member of the carcinogenic aflatoxin family. Our previous studies indicated that oral administration of AFG1 caused tumor necrosis factor (TNF)-〈-dependent inflammation that enhanced oxidative DNA damage in alveolar epithelial cells, which may be related to AFG1-induced lung carcinogenesis. High mobility group box-1 (HMGB1) is a nuclear DNA-binding protein; the intracellular and extracellular roles of HMGB1 have been shown to contribute to DNA repair and sterile inflammation. The role of HMGB1 in DNA damage in an aflatoxin-induced lung inflammatory environment was investigated i...
Source: Toxicology Letters - May 20, 2020 Category: Toxicology Authors: Kang L, Guo N, Liu X, Wang X, Guo W, Xie SM, Liu C, Lv P, Xing L, Zhang X, Shen H Tags: Toxicol Lett Source Type: research

Protection of 6-OHDA neurotoxicity by PGF2 α through FP-ERK-Nrf2 signaling in SH-SY5Y cells.
In this study, we investigated the effects of PGF2α against 6-OHDA-mediated toxicity in human neuroblastoma SH-SY5Y cells and elucidated its underlying molecular mechanism. When the cells were treated with 6-OHDA (50 μM) for 6 h, the expression levels of PGF2α synthetic enzymes; cyclooxygenase-2 and aldo-keto reductase 1C3 as PGF2α synthase were enhanced in an incubation-time-dependent manner. In addition, the production of PGF2α was increased in 6-OHDA-treated cells. Fluprostenol, a PGF2α receptor (FP) agonist (500 nM), suppressed 6-OHDA-induced cell death by decreasing the production of reactive oxygen specie...
Source: Toxicology - January 21, 2021 Category: Toxicology Authors: Sano A, Maehara T, Fujimori K Tags: Toxicology Source Type: research

Susceptibility to DNA Damage Caused by Abrogation of Rad54 homolog B: A Putative Mechanism for Chemically Induced Cleft palate
In this study, mouse embryonic heads were collected on embryonic day (E) 13.5∼16.5. The expression level of DNA repair protein Rad54 homolog B (Rad54B) was significantly decreased while those of the DNA double-strand breaks (DSBs) marker γ-H2A.X, apoptosis marker caspase-3 and p53 were significantly increased in the palatal shelves upon exposure to atRA and TCDD relative to the control. Primary mouse embryonic palatal mesenchymal cells (MEPMs) were cultured and transfected with siRNA or adenovirus in vitro to knock down or increase the level of Rad54B. Rad54B knockdown resulted in increased cellular S-phase arrest and a...
Source: Toxicology - April 6, 2021 Category: Toxicology Authors: Weiwei Qiao Pei Huang Xinhuan Wang Liuyan Meng Source Type: research

Similar frequency and signature of untargeted substitutions induced by abasic site analog under reduced human APE1 conditions
J Toxicol Sci. 2021;46(6):283-288. doi: 10.2131/jts.46.283.ABSTRACTAbasic sites are formed in cells by various factors including environmental mutagens and considered to be involved in cancer initiation, promotion, and progression. A chemically stable abasic site analog (tetrahydrofuran-type analog, THF) induces untargeted base substitutions as well as targeted substitution and large deletion mutations in human cells. The untargeted substitutions may be initiated by the cleavage of the DNA strand bearing THF by the human apurinic/apyrimidinic endonuclease 1 (APE1) protein, the major repair enzyme for THF and abasic sites. ...
Source: Journal of Toxicological Sciences - June 3, 2021 Category: Toxicology Authors: Tetsuya Suzuki Yuri Katayama Yasuo Komatsu Hiroyuki Kamiya Source Type: research

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