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)

Hepatocyte apoptosis is increased in patients with nonalcoholic steatohepatitis and correlates with disease severity. Long-chain saturated fatty acids, such as palmitate and stearate, induce apoptosis in liver cells. The present study examined insulin-mediated protection against saturated fatty acid-induced apoptosis in the rat hepatoma cell line, H4IIE, and primary rat hepatocytes. Cells were provided a control media (no fatty acids) or the same media containing 250 micromol/liter of albumin-bound oleate or palmitate for 16 h. Insulin concentrations were 0, 1, 10, or 100 nmol/liter (n=4-6/treatment). Palmitate, but not oleate, activated caspase-3 and induced DNA fragmentation in the absence of insulin. Insulin reduced palmitate-mediated activation of caspase-3 and DNA fragmentation in a dose-dependent manner. Phosphatidylinositol 3-kinase inhibitors abolished these effects of insulin. Insulin-mediated inhibition of palmitate-induced apoptosis was not due to an augmentation in the unfolded protein response or increased expression of genes encoding the inhibitor of apoptosis proteins, inhibitor of apoptosis protein-2 and X-linked mammalian inhibitor of apoptosis protein. Palmitate, but not oleate, increased c-Jun NH2 terminal kinase activity in the absence of insulin. Insulin or SP600125, a chemical inhibitor of c-Jun NH2 terminal kinase, blocked palmitate-mediated activation of c-Jun NH2 terminal kinase and reduced apoptosis. These data suggest that insulin is an important determinant of saturated fatty acid-induced apoptosis in liver cells and may have implications for fatty acid-mediated liver cell injury in insulin-deficient and/or -resistant states.
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PMID:Insulin protects liver cells from saturated fatty acid-induced apoptosis via inhibition of c-Jun NH2 terminal kinase activity. 1743 Oct 9

Two peptides with differential cytolytic activity against bacteria, a fungus pathogenic to amphibians, and mammalian cells were isolated from norepinephrine-stimulated skin secretions of the Lemur leaf frog Hylomantis lemur Boulenger, 1882. Dermaseptin-L1 (GLWSKIKEAAKAAGKAALNAVTGLVNQGDQPS) was active against the Gram-negative bacterium Escherichia coli (MIC=8 microM) but inactive against the Gram-positive bacterium Staphylococcus aureus. This peptide inhibited growth of zoospores of the chytrid fungus Batrachochytrium dendrobatidis at concentrations above 25 microM but did not completely inhibit growth at 100 microM. Phylloseptin-L1 (LLGMIPLAISAISALSKL.NH2) was active against S. aureus (MIC=8 microM) but was inactive against E. coli. This peptide also inhibited growth of B. dendrobatidis zoospores at concentrations above 25 microM with complete inhibition at 100 microM. Dermaseptin-L1 showed selective cytolytic activity against HepG2 human hepatoma-derived cells (LC50=45 microM) compared with human erythrocytes (LC50=200 microM) whereas phylloseptin-L1 was approximately equipotent against both HepG2 cells (LC50=35 microM) and erythrocytes (LC50=40 microM).
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PMID:Peptides with differential cytolytic activity from skin secretions of the lemur leaf frog Hylomantis lemur (Hylidae: Phyllomedusinae). 1756 Dec 25

Poly(1-vinylimidazole) (PVIm) with aminoethyl groups has been synthesized as a new pH-sensitive polycation to enhance cell-specific gene delivery. The resulting aminated PVIm (PVIm-NH2) was water-soluble despite deprotonation of the imidazole groups at physiological pH, as determined by acid-base titration and solution turbidity measurement. Hemolysis assay showed that PVIm-NH2 enhanced membrane disruptive ability at endosomal pH, owing to the protonation of the imidazole groups with a pKa value around 6.0. Agarose gel retardation assay proved that the introduced aminoethyl groups worked as anchor groups to retain DNA. Furthermore, the ternary complex of DNA, PVIm-NH2, and a poly(L-lysine) conjugated with lactose molecules, PLL-Lac, at pH 7.4 dissociated the PLL-Lac polycation by protonation of the imidazole groups of PVIm-NH2 at pH 6.0. The resulting PVIm-NH2/DNA binary complexes easily released DNA, as compared with the PLL-Lac/PVIm-NH2/DNA ternary complex, which was examined by competitive exchange with dextran sulfate. By using PVIm-NH2 as a pH-sensitive DNA carrier, as well as PLL-Lac as a cell-targeting DNA carrier, the resulting ternary complex specifically mediated the gene expression, which depended on the protonation of the imidazole groups, on human hepatoma HepG2 cells with asialoglycoprotein receptors. These results suggest that the cell-specific gene delivery mediated by PLL-Lac was enhanced by PVIm-NH2 as a new pH-sensitive polycation.
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PMID:Design of aminated poly(1-vinylimidazole) for a new pH-sensitive polycation to enhance cell-specific gene delivery. 1771 34

The signal transducer and activator of transcription 3 (STAT3) is an IL-6-inducible transcription factor that mediates the hepatic acute phase response (APR). Using gamma-fibrinogen (FBG) as a model of the APR, we investigated the requirement of an IL-6-inducible complex of STAT3 with cyclin-dependent kinase 9 (CDK9) on gamma-FBG expression in HepG2 hepatocarcinoma cells. IL-6 induces rapid nuclear translocation of Tyr-phosphorylated STAT3 that forms a nuclear complex with CDK9 in nondenaturing co-immunoprecipitation and confocal colocalization assays. To further understand this interaction, we found that CDK9-STAT3 binding is mediated via both STAT NH2-terminal modulatory and COOH-terminal transactivation domains. Both IL-6-inducible gamma-FBG reporter gene and endogenous mRNA expression are significantly decreased after CDK9 inhibition using the potent CDK inhibitor, flavopiridol (FP), or specific CDK9 siRNA. Moreover, chromatin immunoprecipitation (ChIP) experiments revealed an IL-6-inducible STAT3 and CDK9 binding to the proximal gamma-FBG promoter as well as increased loading of RNA Pol II and phospho-Ser2 CTD Pol II on the TATA box and coding regions. Finally, FP specifically and efficiently inhibits association of phospho-Ser2 CTD RNA Pol II on the gamma-FBG promoter, indicating that CDK9 kinase activity mediates IL-6-inducible CTD phosphorylation. Our data indicate that IL-6 induces a STAT3.CDK9 complex mediated by bivalent STAT3 domains and CDK9 kinase activity is necessary for licensing Pol II to enter a transcriptional elongation mode. Therefore, disruption of IL-6 signaling by CDK9 inhibitors could be a potential therapeutic strategy for inflammatory disease.
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PMID:The functional role of an interleukin 6-inducible CDK9.STAT3 complex in human gamma-fibrinogen gene expression. 1795 65

The poly(1-vinylimidazole) (PVIm) with aminoethyl groups has been synthesized as a new pH-sensitive DNA carrier. The resulting aminated PVIm (PVIm-NH2) was water-soluble in spite of the deprotonation of the imidazole groups at physiological pH, as determined by acid-base titration and solution turbidity measurement. Hemolysis assay showed the PVIm-NH2 enhanced membrane disruptive ability at endosomal pH, owing to the protonation of the imidazole groups with a pKa value around 6.0. Agarose gel retardation assay proved that the introduced aminoethyl groups worked as an anchor groups to retain DNA. The resulting PVIm-NH2 formed the ternary complex with DNA and lactosylated poly(L-lysine), leading to the significant gene expression in human hepatoma HepG2 cells.
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PMID:Synthesis of aminated poly(1-vinylimidazole) for a new pH-sensitive DNA carrier. 1802 22

It is well known that it would be important to cultivate human hepatocytes of about 10(10) cells at a high cell density, about 1 x 10(7) cells/cm(3), in the bioreactor for the development of bioartificial liver. However, since primary human hepatocytes lack an ability to proliferate in vitro, it is essential to establish a culture method for the proliferation of normal human hepatic stem cells as a cell source. In this study, it was found that human hepatoblasts, a kind of hepatic stem cells, were induced from human fetal hepatocytes while keeping the ability of proliferation by the treatment of 1mM sodium butyrate (SB) for 12 d of culture. The transformation of hepatoblasts was evaluated by abnormal prothrombin (PIVKA-II) assay, which is a clinical marker for hepatocellular carcinoma. The PIVKA-II production rate of the cells was suppressed to the normal level under 1 mM SB. The cells including hepatoblasts under 1 mM SB attached to the porous hydroxyapatite carriers and proliferated to a high cell density of about 1 x 10(7) cells/cm(3) in the carriers. The liver-specific function, cytochrome P450 3A4 activity (4.2 pmol/mg protein/min) of the cells in the carriers under 1 mM SB was comparable to that of primary human hepatocytes. Ammonia metabolizing activity (0.21 micromol/10(6) cells/h) of the cells was also comparable to that of porcine hepatocytes used in the bioartificial liver. The PIVKA-II production rate of the cells in the carrier was suppressed to the normal level. These results suggested that induction of human hepatoblasts from fetal hepatocytes by the treatment of 1mM SB and proliferation of the cells at a high cell density using hydroxyapatite carriers should be one of the more promising culture methods for bioartificial liver developments.
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PMID:Induction and high density culture of human hepatoblasts from fetal hepatocytes with suppressing transformation. 1805 17

PEGylation which is reversed after the therapeutic agent reaches the target cell presents an attractive feature for drug, protein or nucleic acid delivery. Amine-reactive, endosomal pH cleavable polyethylene glycol aldehyde-carboxypyridylhydrazone, N-hydroxysuccinimide esters (PEG-HZN-NHS) were synthesized and applied for bioreversible surface shielding of DNA polyplexes. Monofunctional mPEG-HZN-NHS was synthesized by reacting succinimidyl hydraziniumnicotinate with mPEG-butyraldehyde (20 kDa). Bifunctional OPSS-PEG-HZN-NHS was synthesized analogously via a omega-2-pyridyldithio-PEG (10 kDa) propionaldehyde intermediate. Polyethylenimine (PEI) polyplexes were reacted with the pH-sensitive (mPEG-HZN-NHS) or the corresponding stable (mPEG-NHS) reagent. Both types of polyplexes remained shielded at pH 7.4 as demonstrated by particle size and zeta potential measurements after 4h of incubation at 37 degrees C. Polyplex deshielding at endosomal pH 5 was observed only with the mPEG-HZN-NHS shielded particles. This was confirmed by fluorescence correlation spectroscopy using the analogous Alexa-488 fluorescently labeled bifunctional PEGylation reagents. Luciferase gene transfections with epidermal growth factor (EGF) containing polyplexes using EGF-receptor overexpressing hepatoma HUH7 cells showed an up to 16-fold enhancement in gene expression with the reversibly shielded polyplexes as compared to stably shielded polyplexes. Consistently, the reversibly shielded polyplexes mediated also an enhanced tumor specific in vivo transgene expression after intravenous administration in a subcutaneous HUH7 tumor model in SCID mice.
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PMID:Amine-reactive pyridylhydrazone-based PEG reagents for pH-reversible PEI polyplex shielding. 1858 70

Nutritional support may play an important role in management of liver cirrhosis (LC) associated with unresectable hepatocellular carcinoma (HCC). Total protein and albumin deteriorate in patients with LC undergoing trans-arterial chemoembolization (TACE). Therefore, in this study, we examined the hypothesis that short-term administration of branched-chain amino acids (BCAA) will prevent a fall in total protein and albumin in the perioperative period. The subjects were 56 patients who underwent TACE for HCC between 2004 and 2005 at Nagasaki University Hospital. The patients were randomly placed in the BCAA group (n = 28) or a control group (n = 28). The patients in the BCAA group consumed a snack containing 50 g of BCAA once a day at 10:00 pm starting 1 day before TACE and continuing until 2 weeks after TACE. A comparison of baseline and end point data showed greater decreases in the concentrations of total protein, albumin, cholinesterase, and total cholesterol and in the red blood cell count in the control group compared to the BCAA group. Ammonia levels decreased in the BCAA group and increased in the control group. Our findings indicate that a BCAA supplement taken orally as a late evening snack prevents suppression of liver function by TACE in patients with LC complicated with HCC during the 2-week period after TACE.
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PMID:A snack enriched with oral branched-chain amino acids prevents a fall in albumin in patients with liver cirrhosis undergoing chemoembolization for hepatocellular carcinoma. 1928 98

Thrombin has been recently demonstrated to promote hepatocellular carcinoma (HCC) cell migration by activation of the proteinase-activated receptor (PAR) subtypes PAR1 and PAR4 suggesting a role of these proteinase-receptor systems in HCC progression. In this study, we investigated the effect of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic compound of green tea on thrombin-PAR1/PAR4-mediated hepatocellular carcinoma cell invasion and p42/p44 MAPKinase activation. In this study we used the permanent liver carcinoma cell line HEP-3B and two primary cultures established from surgically resected HCCs. We found that stimulation of HCC cells with thrombin, the PAR1-selective activating peptide, TFLLRN-NH2, and the PAR4-selective activating peptide, AYPGKF-NH2, increased cell invasion across a Matrigel-coated membrane barrier and stimulated activation of p42/p44 MAPKinase phosphorylation. Both the effects on p42/p44 MAPKinases, and on cell invasiveness induced by thrombin and the PAR1/4 subtype-selective agonist peptides were effectively blocked by EGCG. The results clearly identify EGCG as a potent inhibitor of the thrombin-PAR1/PAR4-p42/p44 MAPKinase invasive signaling axis in hepatocellular carcinoma cells as a previously unrecognized mode of action for EGCG in cancer cells. Moreover, the results suggest that (-)-epigal-locatechin-3-gallate might have therapeutic potential for hepatocellular carcinoma.
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PMID:Green tea polyphenol epigallocatechin-3-gallate inhibits thrombin-induced hepatocellular carcinoma cell invasion and p42/p44-MAPKinase activation. 1936 Mar 2

The genus Acanthostrongylophora is famous for producing a wide array of manzamine alkaloids as natural hydrochloride salts. An examination of A. ingens has now yielded two tertiary bases, (+)-8-hydroxymanzamine A (1) and (+)-manzamine A (2), by chromatography over alumina using CHCl3-MeOH-NH3.H2O as solvent. In addition, (+)-8-hydroxymanzamine A hydrochloride (3) and (+)-manzamine A hydrochloride (4) were isolated under the same conditions from the same source by silica gel chromatography. The structures of 1-4 were determined from 1D- and 2D-NMR spectra and by circular dichroism experiments, and the spectral features of the bases 1 and 2 were found to be different from those of the salts 3 and 4. Compounds 3 and 4 were deprotonated by both A12O3 and strong base to afford 1 and 2, which were converted again to their respective salts 3 and 4. Both the compounds 1 and 3 showed equally potent in vitro antimalarial activity against chloroquine-sensitive (D6) and -resistant (W2) strains of P. falciparum (IC50 = 19.5 and 22.0 ng/mL vs. 27.0 and 36.5 ng/mL, respectively), while 2 was >3-fold less potent than 4 (IC50 = 20.8 and 25.8 ng/mL vs. 6.1 and 7.3 ng/mL, respectively). Compounds 1, 3 and 4 showed good antimicrobial activities against methicillin-resistant Staphylococcus aureus and Mycobacterium intracellulare and antileishmanial activity against Leishmania donovani promastigotes. In contrast, manzamine A base (2) showed relatively weaker antimicrobial, antileishmanial and cytotoxic activities [towards cancer (HepG2: Human hepatocellular carcinoma or hepatoma), and non-cancer cells (VERO: Monkey kidney fibroblast; LLC-PK11: Pig kidney epithelial)], compared with salt 4.
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PMID:Bioactive (+)-manzamine A and (+)-8-hydroxymanzamine A tertiary bases and salts from Acanthostrongylophora ingens and their preparations. 1937 Sep 20


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