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- The effects of 8-OH-DPAT on neuroinflammation after sarin exposure in mice. [JOURNAL ARTICLE]
- Toxicology 2013 May 18.
Poisoning by organophosphate nerve agents can induce seizures which rapidly become refractory to treatment and result in brain damage. Current therapies have only a narrow time frame for effective administration after poisoning. 5-HT1A agonists were tested for efficacy in mice against a seizure-producing combination of the carboxylesterase inhibitor 2-(o-cresyl)-4H-1: 3: 2-benzodioxaphosphorin-2-oxide (CBDP) and sarin, producing an LD20-40. Administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased glial fibrillary acidic protein (GFAP) staining in mice when administered 1min after CBDP and sarin while other 5-HT1A agonists buspirone and S-14506 were not effective. The reduction in GFAP staining by 8-OH-DPAT remained significant when a single dose was administered two hours after the toxic challenge. In addition, 8-OH-DPAT reversed the increase in the inflammatory factor IL-1β in the dentate gyrus and amygdala but did not reduce positive TUNEL staining in the dentate gyrus. Due to the failure of the two other agonists to provide protection, the 5-HT1A antagonist WAY-100635 was tested. WAY-100635 was found to neither reverse the neuroprotective effects of 8-OH-DPAT nor worsen the damage when given alone, making a role for this receptor unlikely. The neuroprotective effects of 8-OH-DPAT appear to lie within its secondary pharmacology.
- Endogenous A1 Adenosine Receptor Protects Mice from Acute Ethanol-Induced Hepatotoxicity. [JOURNAL ARTICLE]
- Toxicology 2013 May 18.
Previous studies have indicated a critical role of adenosine and its receptors in the pathogenesis of liver diseases. The aim of this study was to determine the contribution of A1 adenosine receptor (A1AR) to acute ethanol-induced hepatotoxicity. Wild-type (WT) and A1AR(-/-) mice were intragastrically administered with ethanol (5g/kg), and hepatic injury was evaluated 6h thereafter. Mice lacking A1AR were more susceptible to ethanol-induced liver damage than WT mice, as evidenced by higher serum transaminase levels and increased extent of histopathological changes. Ethanol induced triglycerides accumulation in the serum and liver, and this accumulation was augmented in A1AR(-/-) mice. Analysis of gene expression in the liver revealed up-regulated mRNA levels of genes related to lipogenesis (including: FAS, SCD1, ACC1, DGAT2, and PPARγ) in A1AR(-/-) mice after ethanol treatment. In addition, lack of A1AR aggravated lipid peroxidation and superoxide dismutase depletion caused by acute ethanol exposure. A subsequent study revealed that, pretreatment with A1AR antagonist DPCPX increases the sensitivity of mice to ethanol-induced liver injury. In conclusion, these results indicated that endogenous A1AR activation protects mice against acute ethanol -induced liver injury by reducing oxidative stress and decreasing lipid accumulation.
- Immunological changes of chronic oral exposure to depleted uranium in mice. [JOURNAL ARTICLE]
- Toxicology 2013 May 6.
Direct ingestion of contaminated soil by depleted uranium (DU) might lead to internal exposure to DU by local populations through hand contamination. The purpose of this study was to assess the immunological changes of long-term exposure to various doses of DU in mice. Three-week-old Kunming mice were divided into the following 4 groups based on the various feeding doses (containing DU): 0 (control group), 3 (DU3 group), 30 (DU30 group), and 300mg/kg feed (DU300 group). After 4 months of exposure, in the DU300 group, the innate immune function decreased, manifesting as decreased secretion of nitric oxide, interleukin (IL)-1β, IL-18, and tumour necrosis factor (TNF)-α in the peritoneal macrophages, as well as reduced cytotoxicity of the splenic natural killer cells. Moreover, the cellular and humoral immune functions were abnormal, as manifested by decreased proliferation of the splenic T cells, proportion of the cluster of differentiation (CD) 3(+) cells, ratio of CD4(+)/CD8(+) cells and delayed-type hypersensitivity, and increased proliferation of the splenic B cells, total serum immunoglobin (Ig) G and IgE, and proportion of splenic mIgM(+)mIgD(+) cells. Through stimulation, the secretion levels of interferon (IFN)-γ and TNF-α in the splenic cells were reduced, and the levels of IL-4 and IL-10 were increased. By comparison, in the DU30 and DU3 groups, the effects were either minor or indiscernible. In conclusions, chronic intake of higher doses of DU (300mg/kg) had a significant impact on the immune function, most likely due to an imbalance in T helper (Th) 1 and Th2 cytokines.
- Involvement of DNA polymerase beta overexpression in the malignant transformation induced by benzo[a]pyrene. [JOURNAL ARTICLE]
- Toxicology 2013 May 4.
OBJECTIVE:To explore the relationship between DNA polymerase β (pol β) overexpression and benzo[a]pyrene (BaP) carcinogenesis.
METHODS:Firstly, mouse embryonic fibroblasts that express wild-type level of DNA polymerase β (pol β cell) and high level of pol β (pol β oe cell) were treated by various concentrations of BaP to determine genetic instability induced by BaP under differential expression levels of pol β. Secondly, malignant transformation of pol β cells by low concentration of BaP (20μM) was determined by soft agar colony formation assay and transformation focus assay. Thirdly, the mRNA and protein levels of BaP-transformed pol β cells (named pol β-T cells) was measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot, and the genetic instability of these cells were examined by HPRT gene mutation assay and random amplified polymorphic DNA (RAPD) assay.
RESULTS:Pol β cells were successfully transformed into malignant pol β-T cells by an exposure to low concentration of BaP for 6 months. Pol β-T cells exhibited increased levels of pol β gene expression, HPRT gene mutation frequency and polymorphisms of RAPD products that were comparable to those of pol β cells.
CONCLUSION:Pol β overexpression and its-associated genetic instability may play a key role in BaP carcinogenesis.
- Doxorubicin induces protein ubiquitination and inhibits proteasome activity during cardiotoxicity. [JOURNAL ARTICLE]
- Toxicology 2013 Apr 29.:23-29.
Anthracycline-induced cardiotoxicity is a clinically complex syndrome that leads to substantial morbidity and mortality for cancer survivors. Despite several years of research, the underlying molecular mechanisms remain largely undefined and thus effective therapies to manage this condition are currently non-existent. This study therefore aimed to determine the contribution of the ubiquitin-proteasome pathway (UPP) and endoplasmic reticulum (ER)-stress within this context. Cardiotoxicity was induced with the use of doxorubicin (DXR) in H9C2 rat cardiomyoblasts (3μM) for 24h, whereas the tumour-bearing GFP-LC3 mouse model was treated with a cumulative dose of 20mg/kg. Markers for proteasome-specific protein degradation were significantly upregulated in both models following DXR treatment, however proteasome activity was lost. Moreover, ER-stress as assessed by increased ER load was considerably augmented (in vitro) with modest binding of DXR with ER. These results suggest that DXR induces intrinsic activation of the UPP and ER stress which ultimately contributes to dysfunction of the myocardium during this phenomenon.
- TCDD induces the expression of insulin-like growth factor binding protein 4 in 5L rat hepatoma cells: A cautionary tale of the use of this cell line in studies on dioxin toxicity. [JOURNAL ARTICLE]
- Toxicology 2013 Apr 29.
Previous quantitative proteomic studies on the actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 5L rat hepatoma cells, a cell model frequently used for investigating the mechanisms of TCDD toxicity, had indicated that dioxin exposure reduced the abundance of numerous proteins which are regulated at the level of protein synthesis initiation. In the present study, we have analysed the mechanism mediating this inhibition. TCDD treatment of the cells largely prevented the activation of eukaryotic translation initiation factor 4E-binding protein 1, a regulator of translation initiation and substrate of the mammalian target of rapamycin (mTOR). By "working upwards" from mTOR, we observed that TCDD inhibited endogenous and IGF-I-induced AKT and ERK activation by interfering with tyrosine phosphorylation of insulin receptor substrate 1. This inhibition was mediated by a TCDD-induced secreted factor which was identified as insulin-like growth factor binding protein 4 (IGFBP-4). The induction of IGFBP-4 protein was dependent on a functional aryl hydrocarbon receptor and was preceded by a rapid increase in the level of IGFBP-4 mRNA indicating that IGFBP-4 is a previously unknown transcriptional target of TCDD in 5L cells. IGFBP-4 was not induced by TCDD in the parental cell line of 5L cells, Fao, and in various closely related rat hepatoma cell lines as well as in other unrelated cell types. Analysis of 5L cell chromosomes by multicolour spectral karyotyping (SKY) revealed that the cells carry several hitherto uncharacterised chromosomal translocations. The observations suggest that in 5L cells the Igfbp-4 gene may have got under the control of a promoter containing dioxin responsive element(s) leading to the induction of IGFBP-4 by TCDD. These findings emphasise a particular caution when interpreting and extrapolating results on the action mechanisms of TCDD obtained in studies using 5L cells as a model system.
- Gender differences in the neurotoxicity of metals in children. [JOURNAL ARTICLE]
- Toxicology 2013 Apr 28.
Gender-related differences in susceptibility to chemical exposure to neurotoxicants have not received sufficient attention. Although a significant number of epidemiological studies on the neurodevelopmental effects of metal exposure has been published in the last twenty years, not many of them have considered the possible gender-specific effects of such exposure. This review is focused on studies where the gender differences in pre- and/or postnatal exposure/s to five metals (mercury, lead, manganese, cadmium, and arsenic) and neurodevelopment were evaluated. We conducted a PubMed search in December 2012 and retrieved 20 studies that met the inclusion criteria. A large body of literature on potential neurodevelopment effects in children due to mercury exposure is available, but, a clear pattern regarding gender differences in neurotoxicity is not elucidated. There is also abundant available information on the gender-specific health effects of lead, and exposure to this metal seems to affect boys more than girls. Information regarding gender differences in susceptibility of manganese, cadmium, and arsenic is still too scarce to draw any definite conclusion. More research is highly warranted about this matter. Environmental epidemiological studies should be designed to quantify differential gender-based exposures and outcomes, and this may provide new insights into prevention strategies.
- 4-Hydroxytamoxifen-stimulated processing of cyclin E is mediated via G protein-coupled receptor 30 (GPR30) and accompanied by enhanced migration in MCF-7 breast cancer cells. [JOURNAL ARTICLE]
- Toxicology 2013 Apr 25.:61-65.
Over-expression of cleaved cyclin E in breast tumors is closely associated with tumor progression and resistance to antiestrogens. 17β-Estradiol (E2) has been recently shown to induce cyclin E processing in breast cancer cells. Tamoxifen has been used in patients with estrogen-sensitive breast cancer, yet resistance to antiestrogens and recurrence will appear in some of the patients after its continued use. We therefore addressed possible effects of tamoxifen on the generation of cleaved cyclin E and its signal mechanism(s) in estrogen-responsive MCF-7 breast cancer cells that express both G protein-coupled protein (GPR) 30 and estrogen receptor α (ERα). 4-Hydroxytamoxifen (OHT, tamoxifen's active form) failed to prevent E2-induced proteolysis of cyclin E and migration, but rather triggered cyclin E cleavage coincident with augmented migration. OHT-induced cyclin E truncation also occurred in SK-BR-3 cells that express GPR30 and lack ERα, but not in MDA-MB-231 cells that express neither GPR30 nor ERα. G1, a specific GPR 30 agonist, caused dramatic proteolysis of cyclin E and enhanced migration. Furthermore, OHT-stimulated cleavage of cyclin E and migration were tremendously attenuated by G15, a GPR30 antagonist, or siRNA against GPR30. In addition, inhibitors for EGFR or ERK1/2 remarkably suppressed OHT-induced truncation of cyclin E, suggesting involvement of EGFR signaling. Collectively, our data indicate that OHT contributes to the production of proteolyzed cyclin E via GPR30 with augmented migration in MCF-7 cells.
- Relationship between protein digestibility and allergenicity: Comparisons of pepsin and cathepsin. [JOURNAL ARTICLE]
- Toxicology 2013 Apr 23.:30-38.
An association between protein allergenicity and resistance to pepsin digestion in the gastrointestinal tract has been proposed. However, although widely accepted, such an association is inconsistent with known labile allergens and resistant nonallergens. Given the central role of antigen presenting cells, and in particular dendritic cells (DC), in the development of allergic responses, the stability of allergens to intracellular processing may be more relevant than resistance to extracellular pepsin digestion. We have characterised the expression by DC of cathepsins (proteolytic enzymes), and compared the proteolytic activity of the most highly expressed cathepsin with pepsin for a range of 9 allergens and 4 putative nonallergens. Cathepsin expression in bone marrow-derived DC (BM-DC) derived from BALB/c strain mice was characterised by flow cytometry; cathepsins D, E and S were identified, with cathepsin D being the most highly expressed. Digestion studies revealed that the majority of allergens (5/9) were pepsin resistant, whereas non-allergens (3/4) were labile. If the generation of pepsin-resistant fragments was considered as a feature of allergenicity, this increased to 7/9 allergens and 4/4 nonallergens. In contrast, most of the proteins examined were resistant to cathepsin digestion, with significant digestion recorded for only 2/9 allergens and 2/4 non-allergens. Chemical reduction (to mimic intracellular reducing conditions) increased the susceptibility of proteins to digestion by cathepsins, but did not improve discrimination between allergens and nonallergens on this basis. These data confirm that there is a general relationship between resistance to digestion with pepsin and allergenicity. The relationship is not absolute, but the information gained from this characteristic does provide useful information in a weight of evidence approach for allergenicity assessment. The most abundant cathepsin detected in antigen processing BM-DC, cathepsin D, is not an appropriate substitute for pepsin. The hypothesis that pepsin stability may be a surrogate for stability to digestion within DC may still hold true, but consideration of a single enzyme in this context is possibly an oversimplification.