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

The up-regulation of heat shock protein (HSP) expression has been proposed as a general biomarker of cellular protection against various environmental stresses and chemicals. The present study investigated the possibility of using HSP70 up-regulation as a biomarker of toxicant exposure in vitro. Cells of a rat hepatoma cell line (FGC4) were exposed to concentrations of 1,3-dichloroacetone, duroquinone, diquat dibromide, menadione, hydrogen peroxide, cadmium chloride (CdCl2) and sodium (meta)arsenite (NaAsO2) that elicited 20-50% cytotoxicity over a 24-hour period, and HSP70 levels were measured by ELISA. Up-regulation of HSP70 expression was demonstrated following treatment with menadione, CdCl2 and NaAsO2, but not with the other chemicals tested. A shorter exposure time (6 hours) and/or the use of non-toxic concentrations reduced the level of HSP70 up-regulation with menadione, CdCl2 and NaAsO2, but did not uncover any up-regulation with the other chemicals. Although the toxicity of the majority of the chemicals tested is believed to involve an oxidative stress component, the results of this study clearly demonstrate that up-regulation of HSP70 expression cannot be used as a general biomarker of toxicant exposure in vitro.
 ...
PMID:Increased heat shock protein 70 expression following toxicant-mediated cytotoxicity: a ubiquitous marker of toxicant exposure? 1618 Sep 85

Genomic PCR reactions were performed to isolate gene sequences of tilapia metallothionein (tiMT) from Oreochromis mossambicus and Oreochromis aureus. Two AP1 binding sites, four metal responsive elements, and a TATA box are the major cis-acting elements identified in the 800-bp 5' flanking region of the tiMTs obtained in this study. The tiMT gene promoter cloned from O. aureus was characterized in vitro using PLHC-1 cell-line, a hepatocellular carcinoma of a desert topminnow (Poecciliopsis lucida), following the administrations of Cd2+, Co2+, Cu2+, Ni2+, Pb2+ and Zn2+. Only Cd2+, Pb2+ and Zn2+ were able to induce the transcription of tiMT gene promoter in PLHC-1 cells in a dose-dependent manner. Zn2+ had the highest fold induction of tiMT gene promoter activity. Deletion mutants were tested for their abilities to drive the transcription of reporter gene following Cd2+ and Zn2+ administrations. However, Cu2+ and Ni2+ also induced the production of hepatic MT mRNA in vivo. Northern blot analysis showed that liver gave the highest fold induction of MT gene expression following the administration of heavy metal ions. These data indicated that hepatic MT mRNA level in tilapia is a potential sensitive biomarker of exposure to various metal ions including Cu2+, Cd2+, Ni2+, Pb2+, Hg2+ and Zn2+ ions.
 ...
PMID:Tilapia metallothionein genes: PCR-cloning and gene expression studies. 1630 56

Cadmium coexists with other metals in various products. Releases of cadmium in the environment occur in parallel to the release of other metals including copper, iron and zinc which also have an essential role in human homeostasis as they participate in various biochemical pathways. We studied the interaction of iron, copper, zinc and calcium channel blockers (nifedipine and verapamil) with cadmium chloride in two hepatoma cell lines (HepG2 and HTC cells) in order to determine if these trace elements can affect CdCl(2) uptake and interfere with its toxicity. Both cell lines were initially exposed to CdCl(2) (0-200 microM) for 2h and the uptake of the metal was determined. Cadmium chloride uptake by HepG2 and HTC cells shows an increase with increasing doses of the metal. Cells were also pretreated with 100 uM of FeCl(2) or ZnCl(2) or CuCl(2) or with a nifedipine/verapamil (100 uM) mixture for 2h and then exposed to 200 uM CdCl(2) for 1h in the presence of the trace elements. The uptake of CdCl(2) was determined as well as the membrane integrity (LDH leakage assay), the cell viability (neutral red assay) and cell proliferation (protein assay). Zinc and calcium channel blockers inhibited the uptake of cadmium chloride by both cell lines. On the other hand iron loading resulted in increased uptake of CdCl(2) by both cell lines whereas copper loading increased the uptake of cadmium chloride from HTC cells and inhibited the uptake by HepG2 cells. These findings are of importance when the effects of cadmium on living organisms are examined since co-exposure to cadmium and other metals can occur.
 ...
PMID:Role of trace elements in cadmium chloride uptake in hepatoma cell lines. 1640 89

The protective effects of betulin (BT) against cadmium (Cd)-induced cytotoxicity have been previously reported. However, the mechanisms responsible for these protective effects are unclear. Therefore, this study investigated the mechanisms responsible for the protection of BT against Cd-induced cytotoxicity in human hepatoma cell lines. The protection of BT against Cd cytotoxicity was more effective in the HepG2 than in the Hep3B cells. The protection of BT on Cd-induced cytotoxicity in the HepG2 cells appeared to be related to the inhibition of apoptosis, as determined by PI staining and DNA fragmentation analysis. The anti-apoptosis exerted by BT involved the blocking of Cd-induced reactive oxygen species (ROS) generation, the abrogation of the Cd-induced Fas upregulation, the blocking of caspase-8-dependent Bid activation, and subsequent inhibition of mitochondrial pathway. The BT pretreatment did not affect the p21 and p53 expression levels, when compared with those of the treated cells with Cd alone. BT induced the transient S phase arrest at an early stage and the G0/G1 arrest at a relatively late stage, but it did not observe the sub-G1 apoptotic peak. In the Hep3B cells, Cd did not induce ROS generation. The BT pretreatment partially inhibited the Cd-induced apoptosis, which was related with the incomplete blockage in caspase-9 or -3 activation, as well as in Bax activation. Taken together, it was found that Cd can induce apoptosis via the Fas-dependent and -independent apoptosis pathways. However, the observed protective effects of BT were clearly more sensitive to Fas-expressing HepG2 cells than to Fas-deficient Hep3B cells.
 ...
PMID:Protection of betulin against cadmium-induced apoptosis in hepatoma cells. 1643 12

Cadmium is a toxic metal and no effective antidote exists at present. The aim of this study was to examine whether sulphur amino acids, involved in glutathione synthesis, can modulate cadmium toxicity in vitro. Two hepatoma cell lines (HepG2 and HTC cells) were exposed to cadmium chloride (0-100 microM) for 8h in control media or in media containing 1mM of homocysteine, cysteine or cystathionine. Cell viability was then assessed with the neutral red assay. In order to assess the mechanism by which homocysteine and cysteine modulate cadmium toxicity their ability to scavenge reactive oxygen species was determined as well as the potential to increase intracellular glutathione levels. The ability of the sulphur amino acids to prevent cadmium uptake by HTC and HepG2 cells was also assessed. The results indicate that homocysteine and cysteine protect efficiently both cell lines from cadmium chloride toxicity whereas cystathionine protects efficiently HTC cells but not HepG2 cells. This effect was shown to be dependent on the dose of each amino acid and increased protection from cadmium was observed with increasing concentrations of homocysteine and cysteine. Both amino acids prevented the formation of reactive oxygen species only when they were administered together with cadmium chloride. In addition homocysteine and cysteine did not increase intracellular glutathione levels. The results indicate that the mechanism by which sulphur amino acids protect from cadmium toxicity in vitro is due to the reduced uptake of the metal by the cells possibly by direct binding to the -SH group of the amino acids.
 ...
PMID:Modulation of cadmium chloride toxicity by sulphur amino acids in hepatoma cells. 1644 73

It is desirable to diagnose hepatocellular carcinoma (HCC) in the early stages during its development since its treatment is usually difficult. We previously proposed a new diagnostic method that made use of the total metallothionein (MT), zinc (Zn), and copper (Cu) concentrations in the liver of the HCC patients. We recently found that MT-1 is involved in the metabolism or detoxification of toxic metals, such as cadmium; on the other hand, MT-2 is responsible for the homeostasis of essential metals such as copper, in experimental models such as Long Evans Cinnamon (LEC) rats. In order to device a better diagnostic method than the one we proposed previously, in this study, we newly propose an improved method that includes the discriminative determination data regarding the MT isomers, namely, MT-1 and MT-2, in the liver of patients with or without HCC as compared with the total MT level. The total MT and Zn concentrations in the HCC patients were confirmed to be significantly lower than those in patients without hepatic disorders (Ctrl). In contrast, Cu concentrations of the HCC patients were higher than those of the Ctrl patients. In addition, in the juxta-tumor portion with HCC, MT-1 concentrations were significantly higher than those of MT-2. In contrast, the MT-1 concentrations in the tumor portion were significantly lower than that in the juxta-tumor portion. In addition, MT-1/MT-2 ratio in the tumor portion was significantly lower than that of the juxta-tumor portion. By using parameters such as concentrations of Cu, Zn, total MT, and MT isomers, we performed the multivariate discriminative analysis (MDA). The results suggest that the concentrations of MT isomers change depending on the progress of the tumor, and information on MT isomers and trace elements is very useful in determining the stage of the chronic hepatic disorder.
 ...
PMID:An improved diagnostic method for chronic hepatic disorder: analyses of metallothionein isoforms and trace metals in the liver of patients with hepatocellular carcinoma as determined by capillary zone electrophoresis and inductively coupled plasma-mass spectrometry. 1650 36

Exposure of cells to toxic chemicals is known to up-regulate the expression of a number of stress proteins (SPs), including metallothionein (MT) and members of the heat shock protein (HSP) family, and this response may allow the development of a fingerprint profile to identify mechanisms of toxicity in an in vitro toxicology setting. To test this hypothesis, three hepatic-derived cell culture systems (rat hepatoma FGC4 cell line, rat hepatocytes, human hepatoma HepG2 cell line) were exposed to cadmium (as CdCl2) and arsenic (as NaAsO2), two compounds believed to exert their toxicity through an oxidative stress mechanism, under conditions of phenotypic anchoring defined as minimal and mild toxicity (approximately 5 and 25% reduction in neutral red uptake, respectively). The expression of six SPs--MT, HSP25/27, HSP40, HSP60, HSP70, and HSP90--was then determined by ELISA. Expression of four of these SPs--MT, HSP25/27, HSP40 and HSP70--was up-regulated in at least one experimental condition. However, the patterns of expression of these four SPs varied across the experimental conditions, according to differences in toxicant concentration and/or level of toxicity, cell-type and toxicant itself. This lack of uniformity in response of a focussed set of mechanistically defensible targets suggests that similar problems may emerge when using more global approaches based on genomics and proteomics, in which problems of redundancy in targets and uncertain mechanistic relevance will be greater.
 ...
PMID:Phenotypic anchoring of arsenic and cadmium toxicity in three hepatic-related cell systems reveals compound- and cell-specific selective up-regulation of stress protein expression: implications for fingerprint profiling of cytotoxicity. 1672 91

Chronic liver diseases are disastrous to health. Many factors are associated with their prevalence, hence endemicity. These are mainly infectious, parasitic and toxic. A survey was conducted in a village south to Cairo. Large industries concerned with iron and steel industry, metals smelting, cement manufacturing and electric station were located north to the village. A systematic random sample of houses was selected. All individuals inside the houses were invited to share in the study. Sample size was 84 individuals. Hepatitis markers were done (HBsAg and anti-HCV antibodies). The levels of some heavy metals were assessed; which were lead, mercury, arsenic, aluminum, manganese, nickel, chromium and cadmium. Levels of some trace elements were assessed. These were copper, iron, selenium and zinc. Aflatoxin B1 was assessed in serum. Assessment of schistosomal circulating antigen and antibodies was carried out. Abdominal ultrasonograghy was done to assess liver condition. Univariate logistic regression analysis was done to assess the association between studied variables and HBsAg or anti-HCV sero-positive subjects. The association between studied variables and bilharzial or fatty liver, diagnosed by ultrasonography, were also assessed. The univariate logistic regression analysis revealed odds ratios at the following results. For HBsAg seropositive subjects, aflatoxin B1, lead, chromium and schistosomal antigen and antibodies were higher than negative ones where odds ratios were; 6.2, 1.6, 1.6, 1.6 and 1.7, respectively. None of the variables showed statistically significant difference. For anti-HCV antibodies sero-positive subjects, aflatoxin B1 and chromium had the highest odds ratios among the studied variables, (odds ratios were 2.5 and 2.4, respectively). Bilharzial liver showed higher significant positivity of anti-HCV antibodies and insignificant decreased level of zinc than negative ones (odds ratios were 7.2 and 4.5, respectively). Fatty liver cases showed higher statistically significant positivity of anti-HCV antibodies and chromium than negative ones. Odds ratios were 8.0 and 7.1, respectively. Statistically significant lower level of aflatoxin B1 was shown in fatty liver than normal liver subjects. Multivariate logistic regression analysis for fatty liver showed that only anti-HCV antibodies sero-positivity had statistically significant odds ratio in comparison to chromium level and aflatoxin B1. It is concluded that some heavy metals, and Aflatoxin B1 had a definite association with liver diseases in the area under study. Having anti-HCV antibodies had a relation with fatty liver and with bilharzial liver more than having HBsAg. It is recommended that environmental management to factories nearby the village is urgently needed to decrease exposure to heavy metals. Prevention of hepatitis infection and aflatoxin exposure through different means is also recommended, other wise health care authorities would be confronted with unusual cases of HCC in the nearby future.
 ...
PMID:A cross sectional study of hepatitis B, C, some trace elements, heavy metals, aflatoxin B1 and schistosomiasis in a rural population, Egypt. 1690 Jun 14

The effect of growth hormone (GH) and cadmium (Cd) on metallothionein (MT) expression was investigated in hepatoma cells. In fish the constitutive isoform MT-B and the metal-responsive MT-A are expressed. Real-time RT-PCR revealed that: Cd up-regulates mostly MT-A, GH slightly induces MT-B and the GH/Cd combination induces synergistically both MTs. Perturbations in Ca2+ levels suppressed or reduced the Cd-induction of MTs and abolished the GH/Cd synergy. Similar results were obtained by inhibition of tyrosine kinases. Also the signaling molecules recruited by the GH receptor responded differently to GH and Cd, with ERKs showing a synergistic activation upon GH/Cd. The following conclusions can be drawn: (1) cytosolic Ca2+ is mainly involved in MT-A regulation; (2) both Ca2+ and tyrosine phosphorylation are essential for Cd-induction and GH/Cd synergy on MTs. The synergy could depend on interactions in different signaling pathways, leading to a differential recruitment of MTF-1 and AP-1 transcription factors.
 ...
PMID:Efects of growth hormone and cadmium on the transcription regulation of two metallothionein isoforms. 1702 46

In order to elucidate the feasibility of predicting liver and kidney target-organ toxicity using in vitro cytotoxicity assay, cytotoxicity of selected chemicals, acetaminophen (AAP), mitomycin (MMC), cupric chloride (CuCl2), phenacetin, cadmium chloride (CdCl2) and aristolochic acid (AA), was studied using human hepatoma (Bel-7402) cells and human renal tubular epithelial (HK-2) cells. Cell viability and mitochondrial permeability transition (MPT) were assessed by the neutral red (NR) assay and laser scanning confocal microscope, respectively. The results of the NR assay indicated that cytotoxicity of hepatoxicants, AAP, MMC and CuCl2 in liver cells was higher than that in kidney cells. Cytotoxicitiy of nephrotoxicant, CdCl2 was lower in liver cells than that in kidney cells, but nephrotoxicant phenacetin and AA was higher cytotoxicity in liver cells than that in kidney cells. The cytotoxicity of AAP and phenacetin was strengthened in the presence of S9 mixture, indicating that they are metabolism-mediated cytotoxicants. All selected chemicals disrupted MPT in dose-dependent manner. Linear regression analysis revealed a good correlation between the IC50 values of cytotoxicity and the EC50 values of MPT in Bel-7402 cells and HK-2 cells (R2 = 0.987 and 0.823, respectively). Cytotoxicity assay in vitro using specific cells show good compatibility with target-organ toxicity in vivo. However, limitations of in vitro cytotoxicity assay are due to its incomplete process of ADME and the defect of predicting chronic toxicity effect after long-term exposure to a chemical.
 ...
PMID:In vitro cytotoxicity assay with selected chemicals using human cells to predict target-organ toxicity of liver and kidney. 1737 46


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>