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)

The aryl hydrocarbon receptor (AhR) is a ligand-activated basic-helix-loop-helix transcription factor that binds polyaromatic hydrocarbons (PAH), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and mediates their toxicity. Binding of PAH to AhR in the cytoplasm triggers a poorly defined transformation step of the receptor into a nuclear transcription factor. In this study, we show that the calcium-dependent cysteine protease calpain plays a major role in the ligand-induced transformation and signaling of AhR. Fluorescence imaging measurements showed that TCDD treatment elevates intracellular calcium, providing the trigger for calpain activation, as measured toward t-butoxycarbonyl-Leu-Met-chloromethylaminocoumarin, a calpain-specific substrate. Inhibition of calpain activity by the N-benzyloxycarbonyl-Val-Phe-aldehyde (MDL28170) blocked the TCDD-induced nuclear translocation of AhR in Hepa1c1c7 mouse hepatoma cell line. Treatment of the human metastatic breast carcinoma cell line MT-2 with MDL28170 and 3-(4-iodophenyl)-2-mercapto-(Z)-2-propenoic acid (PD 150606), two calpain-selective inhibitors, completely abolished the TCDD-induced transactivation of AhR as assessed by transcription of CYP1A1 gene. Previous studies have established that after TCDD-induced transactivation, the AhR undergoes a massive depletion; we show here that selective calpain inhibitors can block this step, which suggests that the ligand-induced down-regulation of the AhR is calpain-dependent. The data presented support a major role for calpain in the AhR transformation, transactivation, and subsequent down-regulation, and provide a possible explanation for many of the reported phenomena of ligand-independent activation of AhR.
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PMID:Calpain mediates the dioxin-induced activation and down-regulation of the aryl hydrocarbon receptor. 1718 82

Transcription factor NF-E2-related factor 2 (Nrf2) regulates antioxidant response element (ARE)-mediated expression and coordinated induction of chemoprotective proteins in response to chemical stress. In this report, we investigated Nrf2 response to low and high dose UVB irradiation. Low dose (7.5 J/m(2)) UVB exposure of mouse hepatoma, mouse keratinocyte, and human skin fibroblast cells led to the nuclear accumulation of Nrf2 and up-regulation of ARE-mediated gene expression. On the contrary, and intriguingly, high dose (20 J/m(2)) UVB exposure of cells led to the nuclear exclusion of Nrf2 and down-regulation of chemoprotective gene expression with possible implications in UVB carcinogenesis. We investigated the mechanism by which high dose UVB induced the nuclear exclusion of Nrf2. Prior treatment with nuclear export inhibitor, leptomycin B, abrogated the UVB-induced nuclear exclusion of Nrf2, indicating that the decrease of Nrf2 in the nucleus was due to the nuclear export of Nrf2. High dose UVB increased the phosphorylation of Nrf2Y568 which stimulated the nuclear export of Nrf2. Mutation of Nrf2Y568 to phenylalanine and src kinase inhibitor PP2 abrogated/reduced the UVB-induced phosphorylation of Nrf2Y568 and nuclear exclusion of Nrf2. Transfection with src family member Fyn small interfering RNA resulted in the nuclear accumulation of Nrf2 and an increase in the expression and UVB induction of ARE-mediated gene expression. UVB exposure also induced the nuclear localization of Fyn. These results suggest that high dose UVB induced the activation/nuclear localization of Fyn which led to increased phosphorylation of Nrf2Y568 and enhanced nuclear export of Nrf2. This resulted in nuclear exclusion of Nrf2 and down-regulation of ARE-mediated chemoprotective gene expression.
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PMID:Low and high dose UVB regulation of transcription factor NF-E2-related factor 2. 3038 12

A new clerodane diterpenoid 16-hydroxycleroda-13-ene-15,16-olide-3-one (1) was isolated from the bark of Polyalthia longifolia var. pendula, along with 23 known compounds and phytosteroids. Among these compounds, 5 - 7, 10, and 24 were obtained for the first time from the family Annonaceae . The structures of the isolated compounds were determined by mass and spectroscopic analysis. The clerodane diterpenoids, 2 - 4, showed significant cytotoxicity towards Hep G2 and Hep 3B hepatoma cell lines. Furthermore, compound 5 exhibited potent anti-inflammatory activity towards formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (fMLP/CB)-induced superoxide generation by neutrophils with IC50 = 0.60 +/- 0.09 microg/mL.
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PMID:Anti-inflammatory and cytotoxic diterpenes from formosan Polyalthia longifolia var. pendula. 1702 8

Proapoptotic stimuli, such as CD95 ligand and hydrophobic bile acids induce an epidermal growth factor receptor (EGFR)-catalyzed tyrosine phosphorylation of CD95-death receptor in hepatocytes, as a prerequisite for CD95-translocation to the plasma membrane, formation of the death-inducing signalling complex and execution of apoptotic cell death. However, the molecular role played by CD95 tyrosine phosphorylation remained unclear. The present study shows that CD95-tyrosine phosphorylation is required for CD95-oligomerization. Fluorescence resonance energy transfer (FRET)-analysis in Huh7 hepatoma cells, which were cotransfected with CD95-YFP/CD95-CFP revealed that stimulation of these cells with CD95 ligand, proapoptotic bile acids or hyperosmolarity resulted within 30 min in an intracellular FRET-signal, suggestive for CD95/CD95-oligomerization. After 120 min the FRET-signal was detected in the plasma membrane, indicating translocation of the CD95/CD95-oligomer to the plasma membrane. CD95/CD95-oligomerization was abolished in presence of AG1478 or a JNK-inhibitory peptide, i.e. maneuvers known to prevent EGFR-catalyzed CD95-tyrosine phosphorylation. Transfection studies with YFP/CFP-coupled CD95-mutants, which contain tyrosine/phenylalanine-exchanges in positions 232 and 291 (CD95(Y232,291F)), revealed that at least one tyrosine (Y(232,291))-phosphorylated CD95 is required for CD95/CD95-oligomerization. FRET-studies in mouse embryonic fibroblasts, which in contrast to Huh7 express endogenous CD95, revealed that EGF, but not CD95L induced EGFR-homomerization, whereas CD95 ligand, but not EGF resulted in EGFR/CD95-heteromerization. These findings suggest that EGFR-catalyzed CD95-tyrosine phosphorylation is involved in the CD95/CD95-oligomerization process, which is induced by proapoptotic stimuli and is required for apoptosis induction.
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PMID:CD95 tyrosine phosphorylation is required for CD95 oligomerization. 1719 92

Our past research developed two N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (Dox) conjugates that became the first synthetic polymer-anticancer conjugates to be evaluated clinically. The first, FCE28068, contained Dox bound to the polymeric carrier via a tetrapeptidic linker (glycine-phenylalanine-leucine-glycine (GFLG)) (Mw approximately 30,000 g/mol; approximately 8 wt % drug), and the second, FCE28069, contained additionally galactosamine (Gal) (Mw approximately 30,000 g/mol; approximately 7.5 wt % Dox) again bound by a GFLG linker. Galactosamine was included to promote hepatocyte/hepatoma targeting via the asialoglycoprotein receptor. Both conjugates showed antitumor activity and were clinically less toxic than free Dox (2-5 fold). However, despite their similar chemical characteristics, the conjugates displayed a significantly different maximum-tolerated dose (MTD) in patients. The aim of this study, therefore, was to use small-angle neutron scattering (SANS) to explore the solution behavior of a small library of HPMA polymer conjugates including FCE28068, FCE28069, and their pharmaceutical formulations, plus as reference compounds HPMA copolymer-GFLG conjugates containing aminopropanol (Ap) or galactosamine (Gal) alone (i.e., without Dox). The SANS data obtained showed that HPMA copolymer-GFLG-Ap conjugates (containing 5 and 10 mol % side chains) showed evidence of polymer aggregation, however, no indication of aggregation was observed for FCE28068 and FCE28069 over the concentration range studied (2.5-50 mg/mL). Clear differences in the scattering behavior for the two conjugates were observed at equivalent concentration. Data were best fitted by a model for polydisperse Gaussian coils, and the HPMA copolymer-Dox conjugate with Gal (FCE28069) exhibited a larger radius of gyration (Rg) (by approximately 2.5 nm) compared to FCE28068. In conclusion, we have shown that SANS will be a valuable tool to elucidate conformation-performance relationships for polymer-drug conjugates.
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PMID:Using small-angle neutron scattering to study the solution conformation of N-(2-hydroxypropyl)methacrylamide copolymer-doxorubicin conjugates. 1741 85

Temporin-1DRa (HFLGTLVNLAKKIL.NH(2)), first isolated from the skin of the California red-legged frog Rana draytonii, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by its toxicity against mammalian cells. The cytolytic properties of cationic alpha-helical peptides are determined by a complex interaction between cationicity, hydrophobicity, conformation, and amphipathicity. This study has investigated the cytolytic properties of conformationally constrained analogs of temporin-1DRa containing alpha-aminoisobutyric acid (Aib) substitutions. Cytolytic activity was determined against the bacteria Escherichia coli and Staphylococcus aureus, the opportunistic yeast pathogen, Candida albicans, human erythrocytes, HepG2 hepatoma-derived cells, and L929 fibroblasts. Aib substitutions at Gly(4), Asn(8), and Ala(10) increased both % helicity, determined in methanol solution, and hydrophobicity resulting in increases in both antimicrobial potencies and toxicities against the mammalian cells. Substitution at Leu(6) resulted in an appreciable decrease in cytolytic activity against all cells whereas the substitutions at His(1), Phe(2), Leu(3), Thr(5), and Val(7) had only minor effects on activity. Substitutions at Leu(9), Ile(13), Leu(14) produced analogs with decreased helicity and hydrophobicity that retained activity against microorganisms but showed appreciably lower cytolytic activities against mammalian cells. In particular, the fourfold increase in therapeutic index [ratio of LC(50) against erythrocytes to minimum inhibitory concentration (MIC) against microorganisms] of [Aib(13)]temporin-1DRa identifies it as a compound with potential for development as a therapeutically valuable anti-infective agent.
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PMID:Effect of aminoisobutyric acid (Aib) substitutions on the antimicrobial and cytolytic activities of the frog skin peptide, temporin-1DRa. 1776 78

We describe a retrospective study of long-term outcome of 46 patients treated and regularly followed in France with 2-(2-nitro-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC) for tyrosinaemia type I. Most had initial good response with normalization of liver function and metabolic parameters. Only one infant had no response to treatment and required liver transplantation. Among the 45 long-term treated patients, three underwent secondary liver transplantation: one for cirrhosis and two because of hepatocellular carcinoma. One of the latter died of transplantation complications, so that the overall survival rate was 97.5%. However, 17 of 45 showed persistent abnormal liver imaging (heterogeneous liver) and 6 had cirrhosis. Furthermore, 15 had persistently elevated levels of alpha-fetoprotein, highlighting the question of the persistent risk of carcinoma. Quality of life was usually good but compliance problems were frequent, mainly regarding the low phenylalanine-tyrosine diet. Few adverse effects were observed. A main concern was the high frequency of cognitive impairment causing schooling problems, which may be related to persistent chronic hypertyrosinaemia. In conclusion, this series confirms that NTBC treatment has clearly improved the vital prognosis and quality of life of tyrosinaemia type I patients but that many late complications persist. Long-term studies are necessary to determine whether this drug may prevent or only delay liver complications, andto survey the possible risks of the drug. A more restricted diet could be necessary to prevent the neurological impact of the disease.
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PMID:NTBC treatment in tyrosinaemia type I: long-term outcome in French patients. 1821 11

1H nuclear magnetic resonance (NMR)-based metabonomics was used to characterize metabolic profiles of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). We found compared to healthy humans, LC and HCC sera had higher levels of acetate, Nacetylglycoproteins, pyruvate, glutamine, alpha-ketoglutarate, glycerol, tyrosine, 1-methylhistidine and phenylalanine, together with lower levels of low-density lipoprotein, isoleucine, valine, acetoacetate, creatine, choline and unsaturated lipids. Scores plot of pattern recognition analysis were capable of distinguishing LC and HCC patients from healthy humans. These results indicate that serum NMR spectra combined with pattern recognition analysis techniques offer an efficient, convenient way of depicting tumor biochemistry, which may be of great benefit to early diagnosis of human malignant diseases using single blood samples.
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PMID:Application of 1H NMR-based metabonomics in the study of metabolic profiling of human hepatocellular carcinoma and liver cirrhosis. 1946 21

Phenylketonuria (PKU), the most frequent disorder of amino acid metabolism, is caused by mutations in human phenylalanine hydroxylase gene (PAH), leading to deficient enzyme activity. Previously reported but uncharacterized PAH gene mutation, p.S231F (c.692C > T), was detected in Serbian patients with classical PKU. We analyzed p.S231F PAH protein in prokaryotic (Escherichia coli) and eukaryotic expression system (hepatoma cells). In both systems the mutant enzyme was unstable. Residual enzyme activity in vitro was approximately 1%. Mutation p.S231F PAH was not activated by pre-incubation with phenylalanine substrate. We found no GroEL/GroES chaperone effect and slightly positive effect of the (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH(4)) on the stabilization of the protein structure. Our findings were in accordance with severe patients' phenotypes. In conclusion, p.S231F should be classified as a functionally null PAH gene mutation as it drastically reduces stability and activity of the PAH enzyme in vitro.
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PMID:The Missense p.S231F phenylalanine hydroxylase gene mutation causes complete loss of enzymatic activity in vitro. 1962 56

Activity-based protein profiling (ABPP) offers direct insight into changes in catalytic activity of enzyme classes in complex proteomes, rather than protein or transcript abundance. Here, ABPP was performed in Huh7 hepatoma cell lines with a group of ABPP probes composed of an N-acetylated amino acid, that mimic the P(1) position in protease peptide substrates. Five different probes bearing distinct amino acids (Ser, Thr, Phe, Glu and His) labeled 54 differentially active proteins, including proteases, other hydrolases, oxidoreductases and isomerases. Four of the six protease families were targeted based on their P(1) substrate preferences. The broader specificity of the labeling observed could be explained by the substrate-based targeting nature and the electrophilic properties of the ABPP probes. When applied to Huh7 cells stably replicating hepatitis C virus (HCV) subgenomic replicon RNA, four proteins showed reduced activity, while three proteins had increased activity during HCV replication. These differentially active hits included carboxylesterase 1, cathepsin D, HSP105, protein disulfide isomerase 1 and A6, chaperonin containing TCP1 and isochorismatase domain containing 1, which demonstrated substrate preferences by being labeled by specific substrate probes. This illustrates the broader activity-based profiling capabilities of these substrate-based probes to reveal novel enzyme candidates and their potential roles during HCV replication.
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PMID:Activity-based proteome profiling of hepatoma cells during hepatitis C virus replication using protease substrate probes. 1995 26


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