Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology

Young, M Brook; DiSilvestro, M R; Sendera, Timothy J.; Freund, John M.; Kriete, Andres; Magnuson, Scott R.

doi:10.1038/sj.tpj.6500147

Cited by 19 publications

(22 citation statements)

References 85 publications

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“…With this in mind, we first wanted to investigate whether calcium had any effect on the machinery needed for NO production in a rat model of humoral hypercalcemia of malignancy. Therefore, we performed a high-quality, oligonucleotide microarray analysis on four samples of total RNA subsequently made into cDNA from cells treated with either 3.5 or 0.5 mM calcium (41). The microarray data showed that H-500 cells treated with 3.5 mM calcium for 18 h exhibited an upregulation of iNOS mRNA compared with those treated with 0.5 mM calcium (P Ͻ 0.05; Table 1).…”

Section: Resultsmentioning

confidence: 99%

Calcium-sensing receptor activation induces nitric oxide production in H-500 Leydig cancer cells

Tfelt-Hansen

Ferreira²,

Yano³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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Nitric oxide (NO) is a versatile second messenger. NO is produced by Leydig cells, where NO is a negative regulator of steroidogenesis. In cancer cells, NO is thought to have mutagenic and proliferative effects. We have previously shown that the calcium-sensing receptor (CaR) has promalignant effects in rat H-500 Leydig cancer cells, a model for humoral hypercalcemia of malignancy. Calcium, the major physiological ligand of the CaR, is a recognized intracellular cofactor in the process of NO production by virtue of its positive modulation of neuronal and endothelial nitric oxide synthase (NOS), but importantly, not of inducible (i) NOS activity. iNOS activity is regulated by changes in its expression level. Therefore, we investigated whether CaR activation changes iNOS expression. We found that high extracellular calcium (Ca[Formula: see text]) upregulates the level of mRNA for iNOS, whereas no change was seen in neuronal or endothelial NOS, as assessed by microarray and real-time PCR, respectively. The high Ca[Formula: see text]-induced iNOS upregulation was also detected by Northern and Western blotting. By quantitative real-time PCR, we showed that calcium maximally upregulates iNOS at 18 h. The effect of calcium was abolished by overexpression of a dominant-negative CaR (R185Q), confirming that the effect of Ca[Formula: see text] was mediated by the CaR. Cells treated with high calcium had higher NO production than those treated with low calcium, as detected with the NO-specific DAF2-AM dye. This was confirmed in single-cell fluorescence determinations using confocal microscopy. In conclusion, high calcium upregulates the levels of iNOS mRNA and protein as well as NO production in H-500 cells, and the effect of Ca[Formula: see text] on iNOS expression is mediated by the CaR.

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Section: Resultsmentioning

confidence: 99%

Calcium-sensing receptor activation induces nitric oxide production in H-500 Leydig cancer cells

Tfelt-Hansen

Ferreira²,

Yano³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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“…It is limited to the degree of visual differentiation that can be achieved by the pathologist and may be affected by diagnostic drift or microscope fatigue. Recently, the use of automated pathology systems to provide the morphologic assessment of the tissue has been investigated to supplement the visual examination by a pathologist Kriete and Boyce, 2003;Young et al, 2003). By using automated tissue scanning microscopes and computer programs designed to identify abnormal tissue morphology, the process of correlating gene expression data and morphologic data may be automated.…”

Section: Comparison Of Morphologic Observations Withmentioning

confidence: 99%

Comparative Hepatic Toxicity: Prechronic/Chronic Liver Toxicity in Rodents

Hardisty

Brix

2005

Toxicol Pathol

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The morphologic assessment of the gross and microscopic appearance of the liver can provide a broad base of knowledge concerning the potential toxicity of a drug or chemical. This information may either lead to an understanding of the underlying mechanism of toxicity or guide further study to discern the mode of action of the hepatotoxicity. In standard regulatory bioassays, toxicity studies are conducted during phase 1 and phase 2 of the development process to define the acute, subchronic and chronic toxicity of the test compound. In the liver, there are a limited number of morphologic changes that can be identified using conventional light microscopy. These morphologic alterations are often characterized as "adaptive," consisting of an exaggerated normal physiologic response; "pharmacologic," consisting of an expected alteration in response to the desired action of the test article; or "adverse," consisting of morphologic alterations that are generally undesired, progressive and deleterious to the normal function of the cell(s) involved. Morphologic evidence of adverse effects may involve hepatocytes, the biliary system, hepatic vasculature, Kupffer cells, or stellate cells (Ito cells). In drug discovery and development programs, it is necessary to utilize a multidisciplinary approach, using different endpoints, to investigate the same or similar biological responses in the liver. This results in large amounts of data that must be organized in a retrievable fashion. In order for such a multidisciplinary approach to succeed, each discipline must organize and generate their data in a manner that is easily used by others in the process. The toxicologic pathologist must develop and use standardized nomenclature and diagnostic criteria when examining the liver so that data from various investigators can be compared in a useful manner.

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“…RNA was extracted by an established protocol (Trizol reagent) from livers harvested at various times from rats rats treated with carbon tetrachloride (CCl 4 ), a well-known toxic compound causing liver damage 2 . Details of these sets were explained in previous reports 3,4 . A portion of each liver was also fixed in formalin, embedded in paraffin, slided and stained with hematoxylin and eosin for histology and automated image analysis.…”

Section: Biochip Technologymentioning

confidence: 99%

Advanced tissue analysis using a combined histomorphometric and gene expression profiling method

Kriete

Boyce

2003

Advanced Biomedical and Clinical Diagnostic Systems

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Analysis of gene expression in carbon tetrachloride-treated rat livers using a novel bioarray technology

Cited by 19 publications

References 85 publications

Calcium-sensing receptor activation induces nitric oxide production in H-500 Leydig cancer cells

Calcium-sensing receptor activation induces nitric oxide production in H-500 Leydig cancer cells

Comparative Hepatic Toxicity: Prechronic/Chronic Liver Toxicity in Rodents

Advanced tissue analysis using a combined histomorphometric and gene expression profiling method

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