Amirhosseini, MehdiAlkaissi, HammoudiHultman, Per A.Havarinasab, Said...
8页
查看更多>>摘要：Exposure to heavy metals may have toxic effects on several human organs causing morbidity and mortality. Metals may trigger or exacerbate autoimmunity in humans. Inbred mouse strains with certain H-2 haplotypes are susceptible to xenobiotic-induced autoimmunity; and their immune response to metals such as mercury, gold, and silver have been explored. Serum antinuclear antibodies (ANA), polyclonal B-cell activation, hypergammaglobulinemia and tissue immune complex deposition are the main features of metal-induced autoimmunity in inbred mice. However, inbred mouse strains do not represent the genetic heterogeneity in humans. In this study, outbred Swiss Webster (SW) mice exposed to gold or mercury salts showed immune and autoimmune responses. Intramuscular injection of 22.5 mg/kg.bw aurothiomalate (AuTM) induced IgG ANA in SW mice starting after 5 weeks that persisted until week 15 although with a lower intensity. This was accompanied by elevated serum levels of total IgG antibodies against chromatin and total histones. Exposure to gold led to development of serum IgG autoantibodies corresponding to H1 and H2A histones, and dsDNA. Both gold and mercury induced polyclonal B-cell activation. Eight mg/L mercuric chloride (HgCl2) in drinking water, caused IgG antinucleolar antibodies (ANoA) after 5 weeks in SW mice accompanied by immune complex deposition in kidneys and spleen. Serum IgG antibodies corresponding to anti-fibrillarin, and anti-PM/Scl-100 antibodies, were observed in mercury-exposed SW mice. Gold and mercury trigger systemic autoimmune response in genetically heterogeneous outbred SW mice and suggest them as an appropriate model to study xenobiotic-induced autoimmunity.
查看更多>>摘要：Long-term exposure to carbon nanotubes (CNTs) has been reported to induce malignant transformation. This study aimed to screen candidate biomarkers for monitoring occupational workers to prevent the development of lung cancer. mRNA (GSE56104) and methylation (GSE153246) profiles of lung epithelial BEAS-2B cells exposed to malignant transformation dose of single-walled CNTs or control medium were downloaded from Gene Expression Omnibus database. A total of 1513 differentially expressed genes (DEGs) and 912 differentially methylated genes (DMGs) were identified using LIMMA method. The weighted correlation network analysis identified blue and turquoise modules were associated with malignant transformation of BEAS-2B cells, 124 DMGs of which were overlapped with DEGs. The mRNA and methylation levels of four methylation-driven DEGs were validated in both lung adenocarcinoma (LUAD) and squamous cell carcinomas (LUSC) of The Cancer Genome Atlas dataset and they were associated with overall survival of LUAD patients. Downregulation of PXMP4 and MCOLN2, while upregulation of MET was confirmed in both LUSC and LUAD via Human Protein Atlas analysis. PXMP4 and MET protein levels were also supported in the proteomic analysis of LUAD. Receiver operating characteristic (ROC) curve analysis showed the combination of four genes may be the optimal biomarker for predicting lung cancer, with the area under ROC curve >0.9. Function analysis revealed BARX2 may interact with CCND1 to regulate cell cycle; MET and PXMP4/MCOLN2 may positively correlate with CCR5/IL-6 or GATA3/HLA-DPB1/HLA-DPA1 to involve immune regulation. In conclusion, these four methylationdriven genes may be candidate prognostic and diagnostic biomarkers for single-walled CNT-related lung cancer.
Harrington, James M.Haines, Laura G.Levine, Keith E.Liyanapatirana, Chamindu...
10页
查看更多>>摘要：Vanadium is a ubiquitous environmental contaminant that exists in multiple oxidation states. Humans are exposed to vanadyl (V4+) and vanadate (V5+) from dietary supplements, food, and drinking water and hence there is a concern for adverse human health. The current investigation is aimed at identifying vanadium oxidation states in vitro and in vivo and internal concentrations following exposure of rats to vanadyl sulfate (V4+) or sodium metavanadate (V5+) via drinking water for 14 d. Investigations in simulated gastric and intestinal fluids showed that V4+ was stable in gastric fluid while V5+ was stable in intestinal fluid. Analysis of rodent plasma showed that the only vanadium present was V4+, regardless of the exposed compound suggesting conversion of V5+ to V4+ in vivo and/or instability of V5+ species in biological matrices. Plasma, blood, and liver concentrations of total vanadium, after normalizing for vanadium dose consumed, were higher in male and female rats following exposure to V5+ than to V4+. Following exposure to either V4+ or V5+, the total vanadium concentration in plasma was 2- to 3-fold higher than in blood suggesting plasma as a better matrix than blood for measuring vanadium in future work. Liver to blood ratios were 4-7 demonstrating significant tissue retention following exposure to both compounds. In conclusion, these data point to potential differences in absorption and disposition properties of V4+ and V5+ salts and may explain the higher sensitivity in rats following drinking water exposure to V5+ than V4+ and highlights the importance of internal dose determination in toxicology studies.
查看更多>>摘要：Chronic exposure to arsenic causes cancers in various organs including the skin, liver, lung, and bladder in humans, but the mechanisms of the multi-organ carcinogenicity of arsenic remain unknown. Natural killer (NK) cells play important roles in the immune surveillance and elimination of tumor cells. Although accumulating evidence has indicated that arsenic has immunosuppressive properties, little is known about the effects of arsenic on the tumoricidal functions of NK cells. We examined the effects of arsenite on the cytotoxic activities of human and mouse NK cells toward target tumor cells. Exposure of human NK-92 cells and primary mouse NK cells to sublethal doses of arsenite reduced the IL-2-activated cytotoxic activities toward human K562 cells and murine YAC-1 cells, respectively. NK cells recognize target cells via integrated signals from both activating and inhibitory receptors and induce apoptosis of target cells via a granzyme/perforin system. We found that exposure of NK-92 cells to arsenite diminished the IL-2-activated down-regulation of the inhibitory receptors, KIR2DL2 and KIR2DL3, and the up-regulation of granzyme B and lymphotoxin-alpha. The IL-2-activated increases in secretion of interferon-gamma and IL-10 were also slightly reduced by arsenite. Thus, arsenite suppressed the IL-2-activated cytotoxic activity of NK cells by disrupting multiple pathways required for the recognition and killing of target tumor cells. Our findings provide new insights into the roles of NK cell-mediated tumor immunity in cancer development by arsenic.
查看更多>>摘要：Cytochrome P450 (CYP) gene expression exhibits large interindividual variation attributable to diverse regulatory factors including microRNAs (miRNAs) and hepatic transcription factors (TFs). We used real-time qPCR with 106 human liver samples to measure the expression and interindividual variation of seven miRNAs and four TFs that have been reported to regulate the expression of CYPs; we also identified factors that influence their expression. The results show that expression of the seven miRNAs and the four TFs exhibits a non-normal distribution and the expression variability is high (89- to 618-fold for miRNA and 12- to 85-fold for TFs). Age contributed to the interindividual variation for miR-148a, miR-27b and miR-34a, whereas cigarette smoking and alcohol consumption significantly reduced HNF4 alpha mRNA levels. Association analysis showed significant correlations among the seven miRNAs as well as the four TFs. Furthermore, we systematically evaluated the impact of the seven miRNAs and four TFs on protein content, mRNA levels, translation efficiency and activity of 10 CYPs. The results show that numerous associations (positive and negative) are present between the seven miRNAs or the four TFs and the 10 CYP phenotypes (as indicated by mRNA, protein and activity); specifically, miR-27b, miR-34a and all four TFs played key roles in the interindividual variation of CYPs. Our results extend previous findings and suggest that miR-27b and miR-34a may be potential direct or indirect master regulators of CYP expression and thereby contribute to the interindividual variations in CYP-mediated drug metabolism.
Felix, Luis M.Luzio, AnaAntunes, LuisCoimbra, Ana M....
10页
查看更多>>摘要：Tricaine methanesulfonate (MS-222) is a commonly used anaesthetic agent for immobilization of aquatic species. However, delayed development and malformations have been observed in 24 hpf (hours post-fertilization) zebrafish embryos after long-term immobilization. Still, no comprehensive study has been described regarding zebrafish exposure to MS-222 during the first hours of development, which are one of the most sensitive life stages to toxicants. Therefore, this research aimed to assess the toxicity of a 24 h exposure to MS-222 on zebrafish embryonic development. Based on the MS-222 LC50, early blastula stage embryos (similar to 2 hpf) were exposed to 0, 12.5, 25 and 50 mg L-1 for 24 h and then allowed to develop up to 144 hpf. The chromatographic analysis showed that this anaesthetic agent bioaccumulates in 26 hpf zebrafish larvae in a concentration-dependent manner. In addition, increased mortalities and skeletal abnormalities were observed at 144 hpf, namely in the highest tested concentration. Yet, no craniofacial anomalies were observed either by alcian blue or calcein staining methods. Independently of the tested concentration, decreased speed and distance travelled were perceived in 144 hpf larvae. At the biochemical level, decreased in vivo reactive oxygen species (ROS) generation and apoptosis was observed. Additionally, catalase activity was increased at 26 hpf while results of mRNA expression showed a decreased gclc transcript content at the same time-point. Overall, data obtained highlight the toxicological risk of MS-222 and support ROS-mediated cell death signalling changes through the elevation of catalase activity as an adaptative or protective response.
Leakey, Julian E. A.Ali, A. AfshanBabb, Amy R.Badgley, Heidi L....
11页
查看更多>>摘要：D-glucosamine is a widely consumed dietary supplement used to promote joint health and treat osteoarthritis. It also stimulates intracellular hexosamine flux and increases transforming growth factor beta 1 (TGF beta 1) mRNA expression and insulin resistance in animal studies. The effects of D-glucosamine exposure were investigated in obese Zucker rats. Male (lepr(fa)/lepr(fa)) Zucker rats were exposed to 30, 120, 300 and 600 mg D-glucosamine HCl per kg/day either alone or with chondroitin sulfate (24, 96, 240 and 480 mg/kg/day respectively) for 90 days. After 4 weeks exposure, these doses produced CMAX D-glucosamine concentrations of up to 24 mu M in tail vein serum concurrent with a transient 30% increase in blood glucose concentration in the 600 mg/kg/day dose group. D-Glucosamine did not significantly alter body weight, blood glucose or serum insulin levels at any dose tested after 13 weeks exposure, but did increase urinary TGF beta 1 concentrations. The Zucker rats developed nephropathy and scrotal sores that were related to their hyperglycemia and obesity, and D-glucosamine exposure exacerbated these conditions to a small extent. The incidence of pulmonary osseous metaplasia was increased in rats exposed to D-glucosamine and a single incidence of adrenal osseous metaplasia was noted in one animal exposed to 600/480 mg D-glucosamine HCl/chondroitin sulfate. These lesions may have been treatment related. These studies suggest that the risk of adverse effects of oral D-glucosamine is small compared to that of hyperglycemia in these animals, but the potential for TGF beta 1-mediated pathologies, such as osseous metaplasia and renal nephropathy may be increased.
查看更多>>摘要：Chronic excessive ethanol consumption is associated with a high incidence of mortality due to ethanol-induced dilated cardiomyopathy, known as alcoholic cardiomyopathy (ACM). Mechanistic studies have demonstrated that apoptosis is key to the pathogenesis of ACM, and endoplasmic reticulum (ER) stress-associated apoptosis contributes to various ethanol-related diseases. Astaxanthin (AST) is a natural carotenoid that exerts an anti-ER stress effect. Importantly, strong evidence has shown that AST induces beneficial effects in various cardiovascular diseases. The present study aimed to investigate whether AST induces beneficial effects on ACM by suppressing cardiac apoptosis mediated by ER stress. We showed that after 2 months of chronic excessive ethanol consumption, mice displayed obvious cardiac dysfunction and morphological changes associated with increased fibrosis, oxidative stress, ER stress and apoptosis. However, cardiac damage above was attenuated in response to AST treatment. The cardioprotective effect of AST against ethanol toxicity was also confirmed in both H9c2 cells and primary cardiomyocytes, indicating that AST-induced protection directly targets cardiomyocytes. Both in vivo and in vitro studies showed that AST inhibited all three ER stress signaling pathways activated by ethanol. Furthermore, administration of the ER stress inhibitor sodium 4-phenylbutyrate (4-PBA) strongly suppressed ethanol-induced cardiomyocyte damage. Interestingly, AST induced further anti-apoptotic effects once co-treated with 4-PBA, indicating that AST protects the heart from ACM partially by attenuating ER stress, but other mechanisms still exist. This study highlights that administration of AST ablated chronic excessive ethanol consumption-induced cardiomyopathy by suppressing cardiac ER stress and subsequent apoptosis.
查看更多>>摘要：11 beta-hydroxysteroid dehydrogenase 2 (11 beta-HSD2) converts active 11 beta-hydroxyglucocorticoids to their inactive 11-keto forms, thereby preventing inappropriate mineralocorticoid receptor activation by glucocorticoids. Disruption of 11 beta-HSD2 activity by genetic defects or inhibitors causes the syndrome of apparent mineralocorticoid excess (AME), characterized by hypokalemia, hypernatremia and hypertension. Recently, the azole antifungals itraconazole and posaconazole were identified to potently inhibit human 11 beta-HSD2, and several case studies described patients with acquired AME. To begin to understand why this adverse drug effect was missed during preclinical investigations, the inhibitory potential of itraconazole, its main metabolite hydroxyitraconazole (OHI) and posaconazole against 11 beta-HSD2 from human and three commonly used experimental animals was assessed. Whilst human 11 beta-HSD2 was potently inhibited by all three compounds (IC50 values in the nanomolar range), the rat enzyme was moderately inhibited (1.5- to 6-fold higher IC50 values compared to human), and mouse and zebrafish 11 beta-HSD2 were very weakly inhibited (IC50 values above 7 mu M). Sequence alignment and application of newly generated homology models for human and mouse 11 beta-HSD2 revealed significant differences in the C-terminal region and the substrate binding pocket. Exchange of the C-terminus and substitution of residues Leu170,Ile172 in mouse 11 beta-HSD2 by the corresponding residues His170,Glu172 of the human enzyme resulted in a gain of sensitivity to itraconazole and posaconazole, resembling human 11 beta-HSD2. The results provide an explanation for the observed species-specific 11 beta-HSD2 inhibition by the studied azole antifungals. The obtained structure-activity relationship information should facilitate future assessments of 11 beta-HSD2 inhibitors and aid choosing adequate animal models for efficacy and safety studies.
查看更多>>摘要：Phytosterol diosgenin (DG) exhibits cholesterol-lowering properties. Few studies focused on the underlying mechanism of DG attenuation of hypercholesterolemia by promoting cholesterol metabolism. To investigate the roles of SRB1/CES-1/CYP7A1/FXR pathways in accelerating cholesterol elimination and alleviating hypercholesterolemia, a rat model of hypercholesterolemia was induced by providing a high-fat diet (HFD). Experimental rat models were randomly divided into a normal control (Con) group, HFD group, low-dose DG (LDG) group (150 mg/kg/d), high-dose DG (HDG) group (300 mg/kg) and Simvastatin (Sim) group (4 mg/kg/d). Body weights, serum and hepatic lipid parameters of rats were tested. The expression levels of scavenger receptor class B type I (SRB1), carboxylesterase-1 (CES-1), cholesterol7 alpha- hydroxylase (CYP7A1), and farnesoid X receptor (FXR) were determined. The results showed that DG reduced weight and lowered lipid levels in HFD-fed rats. Pathological morphology analyses revealed that DG notably improved hepatic steatosis and intestinal structure. Further studies showed the increased hepatic SRB1, CES-1, CYP7A1 and inhibited FXR-mediated signaling in DG-fed rats, which contributing to the decrease of hepatic cholesterol. DG also increased intestinal SRB1 and CES-1, inhibiting cholesterol absorption and promoting RCT. The expression levels of these receptors in the HDG group were higher than LDG and Sim groups. These data suggested that DG accelerated reverse cholesterol transport (RCT) and enhanced cholesterol elimination via SRB1/CES-1/CYP7A1/FXR pathway, and DG might be a new candidate for the alleviation of hypercholesterolemia.
NSTL
Elsevier