Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Triethanolamine is widely used as an ingredient in emulsifiers, thickeners, wetting agents, detergents, and alkalinizing agents in cosmetic products; as a chemical intermediate for anionic and nonionic surfactants and surface active agents in household cleaning agents, textiles, herbicides, pharmaceutical ointments, and other products; as a vulcanization accelerator in the manufacture of rubber; and in many other industrial applications. The National Cancer Institute nominated triethanolamine for study because of its widespread use in cosmetics and other consumer products, its high potential for worker exposure due to its many industrial uses, and its potential for conversion to the carcinogen N -nitrosodiethanolamine. Dermal application was chosen as the route of exposure to mimic the principal means of human exposure to triethanolamine and because considerable systemic exposure is achieved with this route. Male and female F344/N rats and B6C3F1 mice received triethanol amine (purity 98% or greater) by dermal application for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melano gaster, and mouse peripheral blood erythrocytes. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were topically administered 0, 125, 250, 500, or 1,000 mg triethanolamine per kilogram body weight in acetone or 2,000 mg/kg neat triethanolamine, 5 days per week, for 13 weeks. All rats survived to the end of the study. Final mean body weights and weight gains of males and females administered 2,000 mg/kg and the mean body weight gain of females administered 1,000 mg/kg were significantly less than those of the vehicle controls. Clinical observations included irritation, scaliness, and crustiness of the skin at the site of application for males and females. Males also had discoloration, and two males administered 2,000 mg/kg had ulceration at the site of application. Changes in clinical pathology parameters were minor and consistent with inflammation at the site of application. Kidney weights were generally greater in males and females administered 500, 1,000, or 2,000 mg/kg than in the vehicle controls. Microscopic lesions attributed to triethanolamine administration included acanthosis and inflammation at the site of application, nephropathy in females, and hypertrophy of the pituitary gland pars intermedia in males and females. These lesions generally occurred with dose-related increases in incidence and severity in males and females. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were topically administered 0, 250, 500, 1,000, or 2,000 mg triethanolamine per kilogram body weight in acetone or 4,000 mg/kg neat triethanolamine, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weight and weight gain of males in the 250 mg/kg group were less than those of the vehicle controls. Clinical findings were observed only in mice in the 4,000 mg/kg groups and included scaliness, irritation, and discoloration at the site of triethanolamine application for males and females and skin erosion at this site in one male. The absolute kidney and liver weights of males and females administered 4,000 mg/kg were greater than those of the vehicle controls; relative kidney weights of males administered 1,000 mg/kg or greater and females in all dosed groups were also greater than those of the vehicle controls. Microscopic examination of the skin of dosed mice indicated acanthosis and inflammation at the site of application. Acanthosis occurred in all dosed groups and in one vehicle control female; the severity increased with increasing dose in males and females. Inflammation was observed in males and females in the 4,000 mg/kg groups and in one female in the 2,000 mg/kg group. 2-YEAR STUDY IN RATS: Based on the presence of acanthosis and inflammation at the site of application at the higher doses in the 13-week study, triethanolamine doses selected for the 2-year study in rats were 32, 63, and 125 mg/kg for malesr males and 63, 125, and 250 mg/kg for females. Groups of 60 male and 60 female rats were topically administered triethanolamine in acetone 5 days per week for 103 weeks. Ten male and ten female rats from each group were evaluated at 15 months for organ weights and histopathology. Survival, Body Weights, Clinical Findings, and Organ Weights: The survival rate of females in the 250 mg/kg group was slightly less than that of the vehicle controls. The mean body weight of females administered 250 mg/kg ranged from 9% to 12% less than that of the vehicle controls between weeks 73 and 93. Male and female rats receiving triethanolamine had irritated skin at the site of application; in dosed females, the site of application also had a crusty appearance. The number of animals in which these findings were observed increased with increasing dose. At the 15-month interim evaluation, the absolute left and right kidney weights and relative right kidney weight of females administered 250 mg/kg were significantly greater than those of the vehicle controls. Pathology Findings: The incidence of acanthosis at the site of application in males administered 125 mg/kg and the incidences of acanthosis, inflammation, and ulceration in dosed females were greater than in the vehicle controls at the 15-month interim evaluation and at the end of the 2-year study. Males in the 125 mg/kg group also had greater incidences of inflammation and ulceration than the vehicle controls, and females receiving 125 or 250 mg/kg had greater incidences of epidermal erosion than the vehicle controls at 2 years. There were no skin neoplasms at or away from the site of application that were considered related to treatment with triethanolamine. At the end of the study, renal tubule adenomas were observed in seven dosed males and in one vehicle control female and one female in the 63 mg/kg group. One male in the 125 mg/kg group and one female in the 250 mg/kg group had renal tubule hyperplasia. Extended (step-section) evaluation of the kidneys of all male rats revealed additional renal tubule adenomas in one vehicle control male, one male in the 32 mg/kg group, two males in the 63 mg/kg group, and three males in the 125 mg/kg group (including one male from the 15-month interim evaluation). An oncocytoma was also identified in one male in the 32 mg/kg group. Hyperplasia was identified in eight additional vehicle control males and in 19 additional dosed males. The total incidences (combined standard and extended evaluations) of renal tubule adenoma in dosed male rats were slightly greater than the vehicle control incidence (vehicle control, 1/50; 32 mg/kg, 2/50; 63 mg/kg, 6/49; 125 mg/kg, 4/50). The total incidence of hyperplasia in dosed and vehicle control males was similar (9/50, 8/50, 7/49, 6/50). The severity of hyperplasia in males in the 32 and 125 mg/kg groups was greater than that in the vehicle controls. 2-YEAR STUDY IN MICE: Based on dose-related inflammation at the site of application in the 13-week study, triethanolamine doses selected for the 2-year study in mice were 200, 630, and 2,000 mg/kg for males and 100, 300, and 1,000 mg/kg for females. Groups of 60 male and 60 female mice were topically administered triethanolamine in acetone 5 days per week for 103 weeks. Ten male and ten female mice from each group were evaluated at 15 months for organ weights and histopathology. Survival, Body Weights, Clinical Findings, and Organ Weights: Survival rates of all dosed groups of males and females were similar to those of the vehicle controls. The mean body weight of males administered 2,000 mg/kg ranged from 8% to 10% less than that of the vehicle controls from week 69 through the end of the study. Clinical findings included irritation and discoloration of the skin at the site of application for most males in the 2,000 mg/kg group and a few females in the 1,000 mg/kg group; males administered 200 or 630 mg/kg also had skin irritation. At the 15-month interim evaluation, the right kidney weights of male mice that received 630 or 2,000 mg/kg and the left kidney weights of males that received 2,000 mg/kg were significantly greater than those of the vehicle controls. Pathology Findings: Acanthosis and inflammation of the skin were observed at the site of application in male and female mice at the 15-month interim evaluation and at the end of the 2-year study. In males in the 2,000 mg/kg group, the incidences of both lesions were significantly greater than those in the vehicle controls at both time points; however, the severities of acanthosis and inflammation did not increase with dose. At the end of the study, the incidence of inflammation in females in the 1,000 mg/kg group was significantly greater than that in the vehicle controls. One vehicle control male and two males in each of the 630 and 2,000 mg/kg groups had ulcers at the site of application. At the 15-month interim evaluation, hepatocellular carcinomas were observed in dosed and vehicle control males and hepatocellular adenomas in dosed and vehicle control males and females; however, the incidences were not dose related. Nonneoplastic lesions observed at 15 months included foci of cellular alteration in a few dosed males and females; eosinophilic foci were also observed in two vehicle control females. At the end of the 2-year study, females in the 1,000 mg/kg group had significantly greater incidences of hepatocellular adenoma and multiple adenomas and a greater combined incidence of hepatocellular adenoma and carcinoma than the vehicle controls (adenoma: vehicle control, 22/50; 100 mg/kg, 22/50; 300 mg/kg, 24/50; 1,000 mg/kg, 40/50; multiple adenomas: 11/50, 9/50, 13/50, 29/50; combined adenoma and carcinoma: 23/50, 26/50, 28/50, 41/50). Females in the 300 mg/kg group had significantly greater incidences of hepatocellular carcinoma (1/50, 4/50, 7/50, 5/50) and eosinophilic foci (9/50, 10/50, 18/50, 16/50) than the vehicle controls. Incidences of hepatocellular adenoma and multiple adenomas in males in the 2,000 mg/kg group were significantly greater than those in the vehicle controls (adenoma: vehicle control, 27/50; 200 mg/kg, 27/50; 630 mg/kg, 29/50; 2,000 mg/kg, 37/50; multiple adenomas: 17/50, 18/50, 17/50, 29/50). Three males in the 2,000 mg/kg group had hepatoblastomas, and males in this group also had significantly greater incidences of hepatocellular neoplasms (combined) (adenoma, carcinoma, and hepatoblastoma: 31/50, 34/50, 33/50, 42/50) and eosinophilic foci (10/50, 17/50, 11/50, 23/50) than the vehicle controls. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver which suggested an infection with Helicobacter hepaticus. With polymerase chain reaction-based assays and culture, the presence of an organism compatible with H. hepaticus was confirmed. An increased incidence of hepatocellular neoplasms in male mice has been shown to be associated with H. hepaticus infection when hepatitis is also present. Therefore, interpretation of the increased incidence of hepatocellular neoplasms in mice was confounded. GENETIC TOXICOLOGY: Triethanolamine was not mutagenic in any of the in vitro or in vivo short-term tests performed by the NTP. It did not induce mutations in Salmonella typhimurium, and no induction of sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells exposed to triethanolamine was noted. These in vitro tests were conducted with and without S9 metabolic activation. Triethanolamine did not induce sex-linked recessive lethal mutations in germ cells of adult male Drosophila melanogaster exposed by feeding or injection. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples of male and female mice that received dermal applications of triethanolamine for 13 weeks. CONCLUSIONS: Under the conditions of these dermal studies, there was equivocal evidence of carcinogenic activity of triethanolamine in male F344/N rats based on a marginal increase in the incidence of renal tubule cell adenoma. There was no evidence of carcinogenic activity in female F344/N rats receiving 63, 125, or 250 mg triethanolamine per kilogram body weight. The study in male and female B6C3F1 mice was considered inadequate, because the presence of a Helicobacter hepaticus infection complicated inter pretation of the relationship between triethanolamine administration and liver neoplasms in these animals. Dosed rats and mice had varying degrees of acanthosis and inflammation, dosed rats had ulceration, and dosed female rats had epidermal erosion at the site of skin application. Synonyms: Nitrilo-2,2',2"-triethanol; 2,2',2"-nitrilotriethanol; 2,2',2"-nitrilotrisethanol; TEA; triaethanolamin-NG; triethanolamin; triethylolamine; tri(hydroxyethyl)amine; 2,2',2"-trihydroxytriethylamine; trihydroxytriethylamine; tris(hydroxyethyl)amine; tris(2-hydroxyethyl)amine; triethylolamine; trolamine Trade Names: Daltogen; Sterolamide; Thiofaco T-35
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PMID:NTP Toxicology and Carcinogenesis Studies of Triethanolamine (CAS No. 102-71-6) in F344 Rats and B6C3F1 Mice (Dermal Studies). 1259 26

To better understand the mechanism underlying hepatocellular carcinoma (HCC) metastasis and to search for potential markers for HCC prognosis, differential proteome analysis on two HCC cell strains with high and low metastatic potentials, MHCC97-H and MHCC97-L, was conducted using two-dimensional (2-D) gel electrophoresis followed by matrix-assisted laser desorption/time of flight mass spectrometry and liquid chromatography ion trap mass spectrometry. Image analysis of silver-stained 2-D gels revealed that 56 protein spots showed significant differential expression in MHCC97-H and MHCC97-L cells (Student's t-test, P < 0.05) and 4 protein spots were only detected in MHCC97-H cells. Fourteen protein spots were further identified using in-gel tryptic digestion, peptide mass fingerprinting and tandem mass spectrometry. The expressions of pyruvate kinase M2, ubiquitin carboxy-terminal hydrolase L1, laminin receptor 67 kDa, S100 calcium-binding protein A4, thioredoxin and cytokeratin 19 were elevated in MHCC97-H cells. However, manganese superoxide dismutase, calreticulin precursor, cathepsin D, lactate dehydrogenase B, non-metastatic cell protein 1, cofilin 1 and calumenin precursor were down-regulated in MHCC97-H cells. Intriguingly, most of these identified proteins have been reported to be associated with tumor metastasis. The functional implications of alterations in the levels of these proteins are discussed.
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PMID:Proteome analysis of hepatocellular carcinoma cell strains, MHCC97-H and MHCC97-L, with different metastasis potentials. 1504 80

Behaviour of argyrophilic nucleolus organising regions (AgNOR) was estimated in various types of spontaneous and transplantable tumors in animals. The studies were performed on spontaneous epithelial and mesenchymal tumors, malignant and non-malignant, as well as transplantable tumors: Morris hepatoma, mammary gland carcinoma and Yoshid sarcoma. The examinations were made on paraffin sections, using silver-staining method according to Ploton et al. Quantitative assessment was made with computer-aided microscopic image analysis system Multi-Scan Base V.8 for Windows, coupled with Carl Zeiss microscope. It was demonstrated that AgNOR index reflects malignancy of the tumor, since it increases clearly in cancers and sarcomas, both spontaneous and transplantable. The highest AgNOR index--0.13--was noted in the group of spontaneous tumors in epithelial malignant tumors, and in the group of transplantable tumors in mesenchymal tumors (Yoshid sarcoma) it was 0.15. Classification of the studied spontaneous and transplantable tumors into groups of the same histogenesis, though phenotypically different, was aimed at demonstration of the increasing tendency of AgNOR index.
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PMID:Studies on nucleolar organiser regions (AgNors) in selected spontaneous and transplantable animal tumors. 1598 32

We recently developed a sensitive method using biotin-N-maleimide (biotin-NM) as a probe to positively identify oxidized mitochondrial proteins. In this study, biotin-NM was used to identify oxidized cytosolic proteins in alcohol-fed mouse livers. Alcohol treatment for 6 wk elevated the levels of CYP2E1 and nitrotyrosine, a marker of oxidative stress. Markedly increased levels of oxidized proteins were detected in alcohol-fed mouse livers compared to pair-fed controls. The biotin-NM-labeled oxidized proteins from alcohol-exposed mouse livers were subsequently purified with streptavidin-agarose and resolved on 2-DE. More than 90 silver-stained protein spots that displayed differential intensities on 2-D gels were identified by MS. Peptide sequence analysis revealed that many enzymes or proteins involved in stress response, chaperone activity, intermediary metabolism, and antioxidant defense systems such as peroxiredoxin were oxidized after alcohol treatment. Smaller fragments of many proteins were repeatedly detected only in alcohol-fed mice, indicating that many oxidized proteins after alcohol exposure were degraded. Immunoblot results showed that the level of oxidized peroxiredoxin (inactivated) was markedly increased in the alcohol-exposed mouse livers and ethanol-sensitive hepatoma cells compared to the corresponding controls. Our results may explain the underlying mechanism for cellular dysfunction and increased susceptibility to other toxic agents following alcohol-mediated oxidative stress.
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PMID:Increased oxidation and degradation of cytosolic proteins in alcohol-exposed mouse liver and hepatoma cells. 1640 14

CyDye DIGE Fluor saturation dye (saturation dye, GE Healthcare Amersham Biosciences) enables highly sensitive 2-D PAGE. As the dye reacts with all reduced cysteine thiols, 2-D PAGE can be performed with a lower amount of protein, compared with CyDye DIGE Fluor minimal dye (GE Healthcare Amersham Biosciences), the sensitivity of which is equivalent to that of silver staining. We constructed a 2-D map of the saturation dye-labeled proteins of a liver cancer cell line (HepG2) and identified by MS 92 proteins corresponding to 123 protein spots. Functional classification revealed that the identified proteins had chaperone, protein binding, nucleotide binding, metal ion binding, isomerase activity, and motor activity. The functional distribution and the cysteine contents of the proteins were similar to those in the most comprehensive 2-D database of hepatoma cells (Seow et al.., Electrophoresis 2000, 21, 1787-1813), where silver staining was used for protein visualization. Hierarchical clustering on the basis of the quantitative expression profiles of the 123 characterized spots labeled with two charge- and mass-matched saturation dyes (Cy3 and Cy5) discriminated between nine hepatocellular carcinoma cell lines and primary cultured hepatocytes from five individuals, suggesting the utility of saturation dye and our database for proteomic studies of liver cancer.
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PMID:Database of two-dimensional polyacrylamide gel electrophoresis of proteins labeled with CyDye DIGE Fluor saturation dye. 1642 55

A simple, sensitive and highly specific immunoassay has been developed based on surface-enhanced Raman scattering for human alpha-fetoprotein (AFP), a tumor marker for the diagnosis of hepatocellular carcinoma. This strategy combines the Ag/SiO2 core-shell nanoparticles embedded with rhodamine B isothiocyanate dye molecules as Raman tags and the amino group modified silica-coated magnetic nanoparticle as immobilization matrix and separation tool. In the proposed system, a sandwich-type immunoassay was performed between polyclonal antibody functionalized Ag/SiO2 nanoparticle-based Raman tags and monoclonal antibody modified silica-coated magnetic nanoparticles. The presence of the analyte and the reaction between the antigen and antibody can be monitored by the Raman spectra of the Ag/SiO2 tags. Compared to the previous surface-enhanced Raman immunoassays, the main advantage of this strategy lies in two aspects. One is the high stability of Raman tags derived from the silica shell-coated silver core-shell nanostructure. The other is the use of silica-coated magnetic nanoparticles as immobilization matrix and separation tool, thus avoiding complicated pretreatment and washing steps. We have studied in detail the experimental parameters such as the effects of the antibody concentration modified on the Raman tags and on the magnetic particles, and the immunoreaction time. Using this strategy, concentration of human AFP up to 0.12 microg/ml was detected with a detection limit of 11.5 pg/ml.
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PMID:Ag/SiO2 core-shell nanoparticle-based surface-enhanced Raman probes for immunoassay of cancer marker using silica-coated magnetic nanoparticles as separation tools. 1697 Nov 10

The purpose of this study was to identify crown materials and luting agents that would decrease the stress concentrated at the roots of endodontically treated teeth. To this end, natural tooth model (NT), full cast crown model (gold-silver-palladium alloy; MC), polymer-based restorative material crown model (HCC), and all-ceramic crown model (ACC) were constructed. In each model, methyl methacrylate-based resin cement (MMA) and composite cement (CC) were used as luting agents. The magnitudes of von Mises stress of the roots during function were compared. When the luting agent was changed from MMA to CC, von Mises stress in the cervical area decreased by 37.8% for MC, 27.1% for HCC, and 37.0% for ACC. Within the limitations of this study, the combination of HCC and CC gave rise to the lowest stress concentration at the cervical area.
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PMID:Investigation of stress distribution in roots restored with different crown materials and luting agents. 1854 Mar 97

Mice were fed either 13 nm silver nanoparticles or 2-3.5 mum silver microparticles. The livers were then obtained after 3 days and subjected to a histopathological analysis. The nanoparticle-fed and microparticle-fed livers both exhibited lymphocyte infiltration in the histopathological analysis, suggesting the induction of inflammation. In vitro, a human hepatoma cell line (Huh-7) was treated with the same silver nanoparticles and microparticles. The mitochondrial activity and glutathione production were hardly affected. However, the DNA contents decreased 15% in the nanoparticle-treated cells and 10% in the microparticle-treated cell, suggesting a more potent induction of apoptosis by the nanoparticles. From a microarray analysis of the RNA from the livers of the nano- and micro-particle-fed mice, the expression of genes related to apoptosis and inflammation was found to be altered. These gene expression changes in the nanoparticle-treated livers lead to phenotypical changes, reflecting increased apoptosis and inflammation. The changes in the gene expression were confirmed by using a semi-quantitative RT-PCR.
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PMID:Comparison of acute responses of mice livers to short-term exposure to nano-sized or micro-sized silver particles. 1860 78

Cytotoxicity induced by silver nanoparticles (AgNPs) and the role that oxidative stress plays in this process were demonstrated in human hepatoma cells. Toxicity induced by silver (Ag(+)) ions was studied in parallel using AgNO(3) as the Ag(+) ion source. Using cation exchange treatment, we confirmed that the AgNP solution contained a negligible amount of free Ag(+) ions. Metal-responsive metallothionein 1b (MT1b) mRNA expression was not induced in AgNP-treated cells, while it was induced in AgNO(3)-treated cells. These results indicate that AgNP-treated cells have limited exposure to Ag(+) ions, despite the potential release of Ag(+) ions from AgNPs in cell culture. AgNPs agglomerated in the cytoplasm and nuclei of treated cells, and induced intracellular oxidative stress. AgNPs exhibited cytotoxicity with a potency comparable to that of Ag(+) ions in in vitro cytotoxicity assays. However, the toxicity of AgNPs was prevented by use of the antioxidant N-acetylcysteine, and AgNP-induced DNA damage was also prevented by N-acetylcysteine. AgNO(3) treatment induced oxidative stress-related glutathione peroxidase 1 (GPx1) and catalase expression to a greater extent than AgNP exposure, but treatment with AgNO(3) and AgNPs induced comparable superoxide dismutase 1 (SOD1) expression levels. Our findings suggest that AgNP cytotoxicity is primarily the result of oxidative stress and is independent of the toxicity of Ag(+) ions.
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PMID:Oxidative stress-dependent toxicity of silver nanoparticles in human hepatoma cells. 1950 89

Although it has been reported that silver nanoparticles (Ag-NPs) have strong acute toxic effects to various cultured cells, the toxic effects at noncytotoxic doses are still unknown. We, therefore, evaluated in vitro toxicity of Ag-NPs at noncytotoxic doses in human hepatoma cell line, HepG2, based on cell viability assay, micronucleus test, and DNA microarray analysis. We also used polystyrene nanoparticles (PS-NPs) and silver carbonate (Ag2CO3) as test materials to compare the toxic effects with respect to different raw chemical composition and form of silver. The cell viability assay demonstrated that Ag-NPs accelerated cell proliferation at low doses (< 0.5 mg/L), which was supported by the DNA microarray analysis showing significant induction of genes associated with cell cycle progression. However, only Ag-NPs exposure exhibited a significant cytotoxicity at higher doses (> 1.0 mg/L) and induced abnormal cellular morphology, displaying cellular shrinkage and acquisition of an irregular shape. In addition, only Ag-NPs exposure increased the frequency of micronucleus formation up to 47.9 +/- 3.2% of binucleated cells, suggesting that Ag-NPs appear to cause much stronger damages to chromosome than PS-NPs and ionic Ag+. Cysteine, a strong ionic Ag+ ligand, only partially abolished the formation of micronuclei mediated by Ag-NPs and changed the gene expression, indicating that ionic Ag+ derived from Ag-NPs could not fully explain these biological actions. Based on these discussions, it is concluded that both "nanosized particle of Ag" as well as "ionic Ag+" contribute to the toxic effects of Ag-NPs.
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PMID:In vitro toxicity of silver nanoparticles at noncytotoxic doses to HepG2 human hepatoma cells. 1973 16


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