Francesco Feo - Academia.edu (original) (raw)

Papers by Francesco Feo

Research paper thumbnail of S-Adenosylmethionine: From the Discovery of Its Inhibition of Tumorigenesis to Its Use as a Therapeutic Agent

Cells

Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induc... more Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent decrease of S-adenosyl-L-methionine (SAM). This causes non-alcoholic fatty liver disease (NAFLD). SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects. SAM plus betaine improves early viral kinetics and increases interferon-stimulated gene expression in patients with viral hepatitis non-responders to pegIFNα/ribavirin. SAM prevents hepatic cirrhosis, induced by CCl4, inhibits experimental tumors growth and is proapoptotic for hepatocellular carcin...

Research paper thumbnail of Identification of genetic loci controlling hepatocarcinogenesis on rat chromosomes 7 and 10

Neoplastic liver nodules and hepatocellular carcinomas (HCCs) were induced, by "resistant hepatoc... more Neoplastic liver nodules and hepatocellular carcinomas (HCCs) were induced, by "resistant hepatocyte" model, 32 and 70 weeks after initiation with diethylnitrosamine, respectively, in F344 Brown Norway (BN), and (BNxF344)Fl rats. Nodule number/liver (N) did not significantly differ among rat strains, whereas nodule mean volume (V) and nodule volume fraction (VF) were higher in susceptible F344 than in resistant BN and BFF1 strains and were predictive of subsequent development of HCCs. Genomic scanning of 157 backcross BFFlxF344 rats with 190 polymorphic microsatellites, and linkage analysis, revealed two quantitative trait loci (QTL) on chromosomes 7 and 10, which showed significant linkage with VF, and two QTL on chromosomes 4 and 8, which showed suggestive linkage with V and VF. On the basis of phenotypic patterns of homozygous and heterozygous backcross progeny and of allelic distribution pattern, QTL on chromosomes 10, 8, and 4 were tentatively identified as resistance loci, and QTL on chromosome 7 was identified as susceptibility locus for rat hepatocarcinogenesis. An analysis of interactions allowed us to identify additional putative QTL on chromosomes 5 and 8 and suggested an additive effect of loci on chromosomes 10, 8, and 4 for VF and V. These data are the first to identify chromosomal regions containing putative susceptibility/resistance loci for rat hepatocarcinogenesis, which seems to be highly complex in terms of the number of genetic factors involved.

Research paper thumbnail of Mg2+-induced shrinkage in mitochondria isolated from Yoshida ascites hepatoma

Life sciences, Jan 15, 1969

In a previous reaearoh (1) evidence has been provided i:Lat mitochondri8 Isolated from AH-130 aso... more In a previous reaearoh (1) evidence has been provided i:Lat mitochondri8 Isolated from AH-130 asoites hep~atoma,ßormerly swollen by metabolio-dependent or metabolic-independent prooesses,nadergo to apparent ehrinloag~e (as measured by absorbante increments at 520~) after the addition of Mgt+ ions,in the absenoe of ezogenons ATP .The absorbante increments oompletely reverse the swelling state provided that appropriate amounts of Mgt+ sre added, and behave se a phenomenon independent from eleotron-and energy--transfer mechanisms .

Research paper thumbnail of Die Wirkung der 2-Desoxyglucose auf den energetischen Stoffwechsel und auf die Proteinsynthese von Tumorzellen und Normalzellen

Journal of Cancer Research and Clinical Oncology, 1964

Die Wirkung der 2-Desoxy-D-Glucose auf Atmung, aerobe und anaerobe Gärung und Einbau von 2-C14-Gl... more Die Wirkung der 2-Desoxy-D-Glucose auf Atmung, aerobe und anaerobe Gärung und Einbau von 2-C14-Glycin in die Zellproteine von Asciteshepatom, von embryonalen und Knochenmarkzellen wurde untersucht. Die Desoxyglucose ruft in Krebszellen eine totale Hemmung der aeroben Gärung und des Glycineinbaus hervor, ohne die Atmung gegenüber den Kontrollversuchen mit Glucose zu verändern.

Research paper thumbnail of Swelling and shrinking phenomena in mitochondria isolated from rat liver and Yoshida ascites hepatoma

Life Sciences, 1967

Evidence has been presented that tumour nilWohondria suspended in hypotonio media (1) or is the p... more Evidence has been presented that tumour nilWohondria suspended in hypotonio media (1) or is the presence oß tb`yrozine (2) swell

Research paper thumbnail of Symposium Opening Remarks

Toxicologic Pathology, 1984

Research paper thumbnail of Multifocal hepatocellular carcinoma: intrahepatic metastasis or multicentric carcinogenesis?

Annals of translational medicine, 2015

Multifocal Hepatocellular carcinoma (HCC) may be multiple HCCs of multicentric origin (MO) or int... more Multifocal Hepatocellular carcinoma (HCC) may be multiple HCCs of multicentric origin (MO) or intrahepatic metastases (IM) arising from a primary HCC. Numerous attempts to differentiate the two types of multifocal HCC have been made including the valuation of the clinicopathologic characteristics of MO and IM patients and the recurrence time, loss-of-heterozygosity analysis of specific DNA microsatellite loci to distinguish multiclonal MO from IM of monoclonal origin, and the research of diagnostic and progression markers through genomic and proteomic analyses. These approaches, however, have been unsatisfactory hitherto. Recently, a multi-omic analysis of HBV-related multifocal HCCs, including intergraded genomics and transcriptomics, was performed and the results, validated by a cohort of 174 HCC patients, were correlated with HCC clinicopathological data. The two multifocal HCC types were effectively discerned by multi-omics profiling that could predict HCC clonality and aggressi...

Research paper thumbnail of Dissection of Signal Transduction Pathways as a Tool for the Development of Targeted Therapies of Hepatocellular Carcinoma

Reviews on Recent Clinical Trials, 2007

Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. St... more Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, -Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16 INK4A and p53 and TGF-/SMAD signaling. Oncosuppressor genes, including p16 INK4A , E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16 INK4A inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.

Research paper thumbnail of Modulatory effect of glucose-6-phosphate dehydrogenase deficiency on benzo(a)pyrene toxicity and transforming activity for in vitro-cultured human skin fibroblasts

Cancer research, 1984

Human skin fibroblasts isolated in vitro from subjects carrying the Mediterranean variant of gluc... more Human skin fibroblasts isolated in vitro from subjects carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase exhibit an 85% decrease of this enzymatic activity. There is a 26% and a 94% decrease of the hexose monophosphate shunt and of the reduced nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide phosphate ratio, respectively. Incubation with 0.1 mM methylene blue activates the hexose monophosphate shunt 7 times that of normal fibroblasts and only 2.2 times that of glucose 6-phosphate-deficient cells. This behavior is coupled with an increase of the resistance to cell death induced by benzo(a)pyrene, a carcinogen, the activation of which proceeds through a reduced nicotinamide adenine dinucleotide phosphate-dependent arene oxide formation. In contrast, no difference between the normal and the deficient fibroblasts exists as regards the toxic effect of methylnitrosourea, a carcinogen that does not need metabolic activation. A growth-retar...

Research paper thumbnail of Acceptor control ratio of mitochondria

European Journal of Cancer (1965), 1973

Research paper thumbnail of Functional and Structural Alterations of Liver Ergastoplasmic Membranes during DL-Ethionine Hepatocarcinogenesis

SUMMARY Different functional and structural properties of rat liver microsomes were studied durin... more SUMMARY Different functional and structural properties of rat liver microsomes were studied during hepatocarcinogenesis in- duced by 0.25% m-ethionine. During the first to fourth months of ethionine feeding, great decreases of cytochrome P-450 content, reduced nicotinamide adenine dinucleotide phosphate-dependent lipid peroxidation, and aminopyrine demethylase activity occurred. No changes in the reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase activity were observed.

Research paper thumbnail of Models for Liver Cancer

The Cancer Handbook, 2005

Research paper thumbnail of Modulatory Mechanisms of Chemical Carcinogenesis: The Role of the NADPH Pool in the Benzo(a)pyrene Activation

Toxicologic Pathology, 1984

A EST RA CT Human lymphocytes and human skin fibroblasts isolated in vilro from subjects carrying... more A EST RA CT Human lymphocytes and human skin fibroblasts isolated in vilro from subjects carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase (CCPD) exhibit an 86-87% decrease of this enzymatic activity. This is coupled with 51% and 61% decreases of the NADPH/NADP+ ratio in the GCPD-deficient human lymphocytes (HL) and human skin fibroblasts (HSF), respectively. There also occurs a 63-67% decrease of the hexose monophosphate shunt (HMS) in the deficient cells. Incubation with 0.1 mM methylene blue stimulates the HMS of normal HL 15-fold and that of deficient lymphocytes only 2.4-fold. These figures are, respectively, 7 and 2.2 in the case of HSF. This behavior of CCPDdeficient HL and HSF is coupled with an increase of the resistance to the cell death induced by benzo(a)pyrene (BP). This effect is mimicked by the incubation of normal HSF with dehydroepiandrosterone (DEA) which strongly inhibits GCPD. In contrast, no differences between normal and deficient HSF occur as a result of the effect of methylnitrosourea (MNU), a carcinogen that does not need metabolic activation.

Research paper thumbnail of Control of Glucose-6-Phosphate Dehydrogenase Deficiency on the Formation of Mutagenic and Carcinogenic Metabolites Derived from Benzo(a)pyrene

Toxicologic Pathology, 1987

It has been observed that human lymphocytes (HL) and fibroblasts, isolated irt vitro from donors ... more It has been observed that human lymphocytes (HL) and fibroblasts, isolated irt vitro from donors carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase (G6PD), show a great decrease in this enzymaticactivity, the hexose monophosphate shunt, and the NADPHINADP' ratio. This effect is associated with a decreased sensitivity of G6PD-deficient cells to the benzo(a)pyrene (BaP) cytotoxic effect and to a decreased iri vitro transformation of BaP-treated fibroblasts. Further, benzo(a)anthracene (BaA)-induced BaP hydroxylase activity is lower in G6PD-deficient cells, when measured in the presence of endogenous NADPH. It has been hypothesized that the NADPH level could be rate-limiting for the NADPH-dependent steps of BaP metabolic activation. To test this hypothesis, the formation of BaP metabolites was studied in normal and G6PD-deficient HL incubated with the carcinogen. HPLC profiles of organic-soluble metabolites revealed that both types of HL produced all the following known BaP metabolites: 9,lO-, 4,5and 7,8-dihydrodiols, quinones, 9and 3-hydroxy and two peaks of more polar metabolites. There was a great decrease of the various metabolites in the deficient HL. A decrease of total water-soluble BaP metabolites also occurred.

Research paper thumbnail of Alterations of liver ergastoplasmic membranes during DL-ethionine hepatocarcinogenesis. Aminopyrine demethylase activity and ribosome-membrane interaction

Life Sciences, 1974

The activity of microsomal aminopyrine demethylase and the degree of association between ribosome... more The activity of microsomal aminopyrine demethylase and the degree of association between ribosomes and endoplasmic membranes were studied in liver of ethionine-fed rats, as well as in hyperplastic nodules and in hepatoma . In the course of the ethionine-feeding, inhibition of aminopyrine demethylase and increase in the relative amounts of membrane-free ribosomes occurred in liver cells . After 1-3 months from the end of the ethionine feeding, when hyperplastic nodules and hepatoma developed in the liver, a sharp inhibition of aminopyrine demethylase was found in the latter tissues, but not in the surrounding nonnodular liver. At the same time an increase of membrane-free ribosomes occurred in surrounding nonnodular liver, in nodules and in hepatoma . The extent of this alteration, however, was significantly lower in surrounding nonnodular liver than in nodules and in hepatoma . These results are discussed in relation to the problem of the cellular precursors of hepatoma .

Research paper thumbnail of The influence of enrichment with cholesterol on the phagocytic activity of rat macro-phages

The Journal of Pathology, 1976

Male Wistar rats (130-150 g) were used as source of control and to induce hypercholesterolaemia. ... more Male Wistar rats (130-150 g) were used as source of control and to induce hypercholesterolaemia. Hypercholesterolaemic treatment was performed as described elsewhere . The treatment lasted 11-13 wk; at the end of this period hypercholesterolaemia reached its highest level. Macrophages were prepared by injecting rats intraperitoneally

Research paper thumbnail of Benzo(a)pyrene metabolism by lymphocytes from normal individuals and individuals carrying the mediterranean variant of glucose-6-phosphate dehydrogenase

International Journal of Cancer, 1987

In vitro growing human lymphocytes (HL) and fibroblasts, isolated from glucose-6-phosphate dehydr... more In vitro growing human lymphocytes (HL) and fibroblasts, isolated from glucose-6-phosphate dehydrogenase (G6PD).de. ficient subjects (Mediterranean variant), show a sharp decrease in this enzymatic activity and in NADPH:NADP+ ratio. These cells are less able than controls to hydroxylate benzo(a)pyrene (BaP) when tested in the absence of an exogenous NADPH-generating system. They exhibit great resistance to the toxic effect of BaP. G6PD-deficient fibroblasts are less prone than controls to in vitro transformation by BaP. To investigate whether this depends on a decreased production of active BaP metabolites and 6aP:DNA adducts by G6PD-deficient cells, BaP metabolism was studied in G6PDdeficient HL cultured in vitro in the presence of mitogens and treated with BaP for 24 hr. HPLC profiles of organo-and water-soluble metabolites revealed that both types of benzo(a)anthracene (6aA)-induced HL produced: 4,5-, 7.8-, 9,IO-diols. l,3-, 3,6-quinones, 3-, 9-hydroxy and 2 peaks of more polar metabolites. There was a 25-76% decrease of organoand water-soluble metabolites in the G6PD-deficient cells. When H L were incubated with 7,8-diol, the formation of metabolites mutagenic for Salmonella typhimurium (His-) was very low in G6PD-deficient cells. 6aP:deoxyadenosine (dAde) and BaPdeoxyaguanosine (dGua) adducts were identified after incubation of both types of HL with BaP. There was a 31.79% fall in adduct formation by G6PD-deficient cells. Our results indicate that G6PD-deficient human lymphocytes are less able to metabolize BaP than normal lymphocytes. We suggest that the NADPH pool is inadequate, in deficient cells, for active BaP metabolism.

Research paper thumbnail of Effect of a cholesterol-rich diet on cholesterol content and phagocytic activity of rat macrophages

Agents and Actions, 1976

Treatment for 11-13 weeks with a cholesterol-rich diet induced increases in free and esterified s... more Treatment for 11-13 weeks with a cholesterol-rich diet induced increases in free and esterified serum cholesterol. There was also an increase in free cholesterol of peritoneal macrophages. A 2.2 times rise in the cholesterol to phospholipid ratio of plasma membranes occurred in cholesterol-enriched macrophages. No changes were observed in phagolysosomes. Cholesterol-enriched macrophages showed a 35.8% inhibition of latex particles phagocytosis. When lipid droplets were substituted for latex the inhibition was 81.7%.

Research paper thumbnail of Phenobarbital stimulation of cytochrome P-450 and aminopyrine N-demethylase in hyperplastic liver nodules during LD-ethionine carcinogenesis

Cancer Letters, 1978

Microsomes isolated from hyperplastic liver nodules and hepatomas, induced by DL-ethionine, exhib... more Microsomes isolated from hyperplastic liver nodules and hepatomas, induced by DL-ethionine, exhibited a reduced cytochrome P-450 content and aminopyrine N-demethylase activity when compared to the organelles of control and surrounding non-nodular liver. Phenobarbital administration to rats caused an increase of microsomal protein, cytochrome P-450 and aminopyrine N-demethylase in all tissue tested. In the hepatoma the rise of cytochrome P-450 and aminopyrine N-demethylase/g of tissue was very low and it is compensated by a slight increase of microsomal protein. In hyperplastic nodules as well as in control and surrounding livers, cytochrome P-450 and aminopyrine N-demethylase increased more than microsomal protein. However, the phenobarbital-induced stimulation was significantly lower in hyperplastic nodules than in control and surrounding livers.

Research paper thumbnail of Effect of cholesterol content on some physical and functional properties of mitochondria isolated from adult rat liver, fetal liver, cholesterol-enriched liver and hepatomas AH-130, 3924A and 5123

Biochimica et Biophysica Acta (BBA) - Biomembranes, 1975

The cholesterol to phospholipid ratio in mitochondria from hepatomas AH-130, 3924A and 5123 is hi... more The cholesterol to phospholipid ratio in mitochondria from hepatomas AH-130, 3924A and 5123 is higher than in the particles isolated from adult or fetal rat livers. Nearly all the cholesterol of hepatoma mitochondria is located in membranes. As in liver mitochondria, in the particles isolated from hepatoma AH-130 there is more cholesterol in the outer than in the inner membrane. In mitochondria from cholesterol-enriched liver and hepatomas, there occurs a decrease in extent of hypoosmotic and phosphate-induced swelling and a decrease of conformational changes linked to energy states. The phenomenon is more marked in particles which exhibit higher cholesterol to phospholipid ratios. A statistically significant negative correlation exists between the cholesterol to phospholipid ratio and extent of volume or conformational changes. No significant modifications of these parameters were found in fetal liver mitochondria. Cholesterol content does not influence K+ uptake by cholesterol-enriched or hepatoma mitochondria. Nor does cholesterol content affect the respiratory increment related to this uptake. As a consequence of K+ uptake, total mitochondrial water exchangeable with tritiated water rises 20% while sucrose-impermeable water rises 42-48% in both adult rat liver and hepatoma AH-130 mitochondria. Absorbance changes linked to ion uptake do not correspond merely to variations in mitochondrial water content. Water content is apparently not influenced by the cholesterol to phospholipid ratio. However, the ratio is significantly correlated to both extent and initial rate of absorbance decrease of mitochondrial suspensions during K+ uptake. The higher the ratio, the lower the extent and initial rate of absorbance decrease.

Research paper thumbnail of S-Adenosylmethionine: From the Discovery of Its Inhibition of Tumorigenesis to Its Use as a Therapeutic Agent

Cells

Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induc... more Alterations of methionine cycle in steatohepatitis, cirrhosis, and hepatocellular carcinoma induce MAT1A decrease and MAT2A increase expressions with the consequent decrease of S-adenosyl-L-methionine (SAM). This causes non-alcoholic fatty liver disease (NAFLD). SAM administration antagonizes pathological conditions, including galactosamine, acetaminophen, and ethanol intoxications, characterized by decreased intracellular SAM. Positive therapeutic effects of SAM/vitamin E or SAM/ursodeoxycholic acid in animal models with NAFLD and intrahepatic cholestasis were not confirmed in humans. In in vitro experiments, SAM and betaine potentiate PegIFN-alpha-2a/2b plus ribavirin antiviral effects. SAM plus betaine improves early viral kinetics and increases interferon-stimulated gene expression in patients with viral hepatitis non-responders to pegIFNα/ribavirin. SAM prevents hepatic cirrhosis, induced by CCl4, inhibits experimental tumors growth and is proapoptotic for hepatocellular carcin...

Research paper thumbnail of Identification of genetic loci controlling hepatocarcinogenesis on rat chromosomes 7 and 10

Neoplastic liver nodules and hepatocellular carcinomas (HCCs) were induced, by "resistant hepatoc... more Neoplastic liver nodules and hepatocellular carcinomas (HCCs) were induced, by "resistant hepatocyte" model, 32 and 70 weeks after initiation with diethylnitrosamine, respectively, in F344 Brown Norway (BN), and (BNxF344)Fl rats. Nodule number/liver (N) did not significantly differ among rat strains, whereas nodule mean volume (V) and nodule volume fraction (VF) were higher in susceptible F344 than in resistant BN and BFF1 strains and were predictive of subsequent development of HCCs. Genomic scanning of 157 backcross BFFlxF344 rats with 190 polymorphic microsatellites, and linkage analysis, revealed two quantitative trait loci (QTL) on chromosomes 7 and 10, which showed significant linkage with VF, and two QTL on chromosomes 4 and 8, which showed suggestive linkage with V and VF. On the basis of phenotypic patterns of homozygous and heterozygous backcross progeny and of allelic distribution pattern, QTL on chromosomes 10, 8, and 4 were tentatively identified as resistance loci, and QTL on chromosome 7 was identified as susceptibility locus for rat hepatocarcinogenesis. An analysis of interactions allowed us to identify additional putative QTL on chromosomes 5 and 8 and suggested an additive effect of loci on chromosomes 10, 8, and 4 for VF and V. These data are the first to identify chromosomal regions containing putative susceptibility/resistance loci for rat hepatocarcinogenesis, which seems to be highly complex in terms of the number of genetic factors involved.

Research paper thumbnail of Mg2+-induced shrinkage in mitochondria isolated from Yoshida ascites hepatoma

Life sciences, Jan 15, 1969

In a previous reaearoh (1) evidence has been provided i:Lat mitochondri8 Isolated from AH-130 aso... more In a previous reaearoh (1) evidence has been provided i:Lat mitochondri8 Isolated from AH-130 asoites hep~atoma,ßormerly swollen by metabolio-dependent or metabolic-independent prooesses,nadergo to apparent ehrinloag~e (as measured by absorbante increments at 520~) after the addition of Mgt+ ions,in the absenoe of ezogenons ATP .The absorbante increments oompletely reverse the swelling state provided that appropriate amounts of Mgt+ sre added, and behave se a phenomenon independent from eleotron-and energy--transfer mechanisms .

Research paper thumbnail of Die Wirkung der 2-Desoxyglucose auf den energetischen Stoffwechsel und auf die Proteinsynthese von Tumorzellen und Normalzellen

Journal of Cancer Research and Clinical Oncology, 1964

Die Wirkung der 2-Desoxy-D-Glucose auf Atmung, aerobe und anaerobe Gärung und Einbau von 2-C14-Gl... more Die Wirkung der 2-Desoxy-D-Glucose auf Atmung, aerobe und anaerobe Gärung und Einbau von 2-C14-Glycin in die Zellproteine von Asciteshepatom, von embryonalen und Knochenmarkzellen wurde untersucht. Die Desoxyglucose ruft in Krebszellen eine totale Hemmung der aeroben Gärung und des Glycineinbaus hervor, ohne die Atmung gegenüber den Kontrollversuchen mit Glucose zu verändern.

Research paper thumbnail of Swelling and shrinking phenomena in mitochondria isolated from rat liver and Yoshida ascites hepatoma

Life Sciences, 1967

Evidence has been presented that tumour nilWohondria suspended in hypotonio media (1) or is the p... more Evidence has been presented that tumour nilWohondria suspended in hypotonio media (1) or is the presence oß tb`yrozine (2) swell

Research paper thumbnail of Symposium Opening Remarks

Toxicologic Pathology, 1984

Research paper thumbnail of Multifocal hepatocellular carcinoma: intrahepatic metastasis or multicentric carcinogenesis?

Annals of translational medicine, 2015

Multifocal Hepatocellular carcinoma (HCC) may be multiple HCCs of multicentric origin (MO) or int... more Multifocal Hepatocellular carcinoma (HCC) may be multiple HCCs of multicentric origin (MO) or intrahepatic metastases (IM) arising from a primary HCC. Numerous attempts to differentiate the two types of multifocal HCC have been made including the valuation of the clinicopathologic characteristics of MO and IM patients and the recurrence time, loss-of-heterozygosity analysis of specific DNA microsatellite loci to distinguish multiclonal MO from IM of monoclonal origin, and the research of diagnostic and progression markers through genomic and proteomic analyses. These approaches, however, have been unsatisfactory hitherto. Recently, a multi-omic analysis of HBV-related multifocal HCCs, including intergraded genomics and transcriptomics, was performed and the results, validated by a cohort of 174 HCC patients, were correlated with HCC clinicopathological data. The two multifocal HCC types were effectively discerned by multi-omics profiling that could predict HCC clonality and aggressi...

Research paper thumbnail of Dissection of Signal Transduction Pathways as a Tool for the Development of Targeted Therapies of Hepatocellular Carcinoma

Reviews on Recent Clinical Trials, 2007

Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. St... more Genomic instability during hepatocarcinogenesis causes changes in signal transduction network. Strategies for identification of new markers/therapeutic targets include discovery of early molecular changes during hepatocarcinogenesis, relevant to preneoplastic lesions progression to full malignancy in rodent models, and evaluation of these changes in human hepatocellular carcinomas (HCCs). Activation of ERB receptor family, MAPK, JAK-STAT, -Catenin cascades, c-Myc targets, iNOS-IKK/MAT1A-NF-kB axis, Ornithine decarboxylase, Cyclins and CDKs occurs in human and rodent hepatocarcinogenesis. This is associated with downregulation of the cell cycle inhibitors p16 INK4A and p53 and TGF-/SMAD signaling. Oncosuppressor genes, including p16 INK4A , E-CAD, and DLC-1 are often hypermethylated in humans and rodents. Moreover, protection of cell cycle from p16 INK4A inhibition by upregulation of CDC37, HSP90, and CRM1 correlates to HCC progression. A body of evidence indicates that inhibition of key genes of aforementioned signaling pathways by antisense or siRNA approaches or specific inhibitors restraints growth of in vitro cultured or in vivo xenografted HCCs. Efforts are currently dedicated to improve transduction efficiency. HCC cells may escape gene therapy by various mechanisms. Attempts to overcome this difficulty include discovery of new therapeutic targets, gene therapy directed to different molecular targets essential for tumor cell survival and specifically directed to HCC subtypes.

Research paper thumbnail of Modulatory effect of glucose-6-phosphate dehydrogenase deficiency on benzo(a)pyrene toxicity and transforming activity for in vitro-cultured human skin fibroblasts

Cancer research, 1984

Human skin fibroblasts isolated in vitro from subjects carrying the Mediterranean variant of gluc... more Human skin fibroblasts isolated in vitro from subjects carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase exhibit an 85% decrease of this enzymatic activity. There is a 26% and a 94% decrease of the hexose monophosphate shunt and of the reduced nicotinamide adenine dinucleotide phosphate/nicotinamide adenine dinucleotide phosphate ratio, respectively. Incubation with 0.1 mM methylene blue activates the hexose monophosphate shunt 7 times that of normal fibroblasts and only 2.2 times that of glucose 6-phosphate-deficient cells. This behavior is coupled with an increase of the resistance to cell death induced by benzo(a)pyrene, a carcinogen, the activation of which proceeds through a reduced nicotinamide adenine dinucleotide phosphate-dependent arene oxide formation. In contrast, no difference between the normal and the deficient fibroblasts exists as regards the toxic effect of methylnitrosourea, a carcinogen that does not need metabolic activation. A growth-retar...

Research paper thumbnail of Acceptor control ratio of mitochondria

European Journal of Cancer (1965), 1973

Research paper thumbnail of Functional and Structural Alterations of Liver Ergastoplasmic Membranes during DL-Ethionine Hepatocarcinogenesis

SUMMARY Different functional and structural properties of rat liver microsomes were studied durin... more SUMMARY Different functional and structural properties of rat liver microsomes were studied during hepatocarcinogenesis in- duced by 0.25% m-ethionine. During the first to fourth months of ethionine feeding, great decreases of cytochrome P-450 content, reduced nicotinamide adenine dinucleotide phosphate-dependent lipid peroxidation, and aminopyrine demethylase activity occurred. No changes in the reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase activity were observed.

Research paper thumbnail of Models for Liver Cancer

The Cancer Handbook, 2005

Research paper thumbnail of Modulatory Mechanisms of Chemical Carcinogenesis: The Role of the NADPH Pool in the Benzo(a)pyrene Activation

Toxicologic Pathology, 1984

A EST RA CT Human lymphocytes and human skin fibroblasts isolated in vilro from subjects carrying... more A EST RA CT Human lymphocytes and human skin fibroblasts isolated in vilro from subjects carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase (CCPD) exhibit an 86-87% decrease of this enzymatic activity. This is coupled with 51% and 61% decreases of the NADPH/NADP+ ratio in the GCPD-deficient human lymphocytes (HL) and human skin fibroblasts (HSF), respectively. There also occurs a 63-67% decrease of the hexose monophosphate shunt (HMS) in the deficient cells. Incubation with 0.1 mM methylene blue stimulates the HMS of normal HL 15-fold and that of deficient lymphocytes only 2.4-fold. These figures are, respectively, 7 and 2.2 in the case of HSF. This behavior of CCPDdeficient HL and HSF is coupled with an increase of the resistance to the cell death induced by benzo(a)pyrene (BP). This effect is mimicked by the incubation of normal HSF with dehydroepiandrosterone (DEA) which strongly inhibits GCPD. In contrast, no differences between normal and deficient HSF occur as a result of the effect of methylnitrosourea (MNU), a carcinogen that does not need metabolic activation.

Research paper thumbnail of Control of Glucose-6-Phosphate Dehydrogenase Deficiency on the Formation of Mutagenic and Carcinogenic Metabolites Derived from Benzo(a)pyrene

Toxicologic Pathology, 1987

It has been observed that human lymphocytes (HL) and fibroblasts, isolated irt vitro from donors ... more It has been observed that human lymphocytes (HL) and fibroblasts, isolated irt vitro from donors carrying the Mediterranean variant of glucose-6-phosphate dehydrogenase (G6PD), show a great decrease in this enzymaticactivity, the hexose monophosphate shunt, and the NADPHINADP' ratio. This effect is associated with a decreased sensitivity of G6PD-deficient cells to the benzo(a)pyrene (BaP) cytotoxic effect and to a decreased iri vitro transformation of BaP-treated fibroblasts. Further, benzo(a)anthracene (BaA)-induced BaP hydroxylase activity is lower in G6PD-deficient cells, when measured in the presence of endogenous NADPH. It has been hypothesized that the NADPH level could be rate-limiting for the NADPH-dependent steps of BaP metabolic activation. To test this hypothesis, the formation of BaP metabolites was studied in normal and G6PD-deficient HL incubated with the carcinogen. HPLC profiles of organic-soluble metabolites revealed that both types of HL produced all the following known BaP metabolites: 9,lO-, 4,5and 7,8-dihydrodiols, quinones, 9and 3-hydroxy and two peaks of more polar metabolites. There was a great decrease of the various metabolites in the deficient HL. A decrease of total water-soluble BaP metabolites also occurred.

Research paper thumbnail of Alterations of liver ergastoplasmic membranes during DL-ethionine hepatocarcinogenesis. Aminopyrine demethylase activity and ribosome-membrane interaction

Life Sciences, 1974

The activity of microsomal aminopyrine demethylase and the degree of association between ribosome... more The activity of microsomal aminopyrine demethylase and the degree of association between ribosomes and endoplasmic membranes were studied in liver of ethionine-fed rats, as well as in hyperplastic nodules and in hepatoma . In the course of the ethionine-feeding, inhibition of aminopyrine demethylase and increase in the relative amounts of membrane-free ribosomes occurred in liver cells . After 1-3 months from the end of the ethionine feeding, when hyperplastic nodules and hepatoma developed in the liver, a sharp inhibition of aminopyrine demethylase was found in the latter tissues, but not in the surrounding nonnodular liver. At the same time an increase of membrane-free ribosomes occurred in surrounding nonnodular liver, in nodules and in hepatoma . The extent of this alteration, however, was significantly lower in surrounding nonnodular liver than in nodules and in hepatoma . These results are discussed in relation to the problem of the cellular precursors of hepatoma .

Research paper thumbnail of The influence of enrichment with cholesterol on the phagocytic activity of rat macro-phages

The Journal of Pathology, 1976

Male Wistar rats (130-150 g) were used as source of control and to induce hypercholesterolaemia. ... more Male Wistar rats (130-150 g) were used as source of control and to induce hypercholesterolaemia. Hypercholesterolaemic treatment was performed as described elsewhere . The treatment lasted 11-13 wk; at the end of this period hypercholesterolaemia reached its highest level. Macrophages were prepared by injecting rats intraperitoneally

Research paper thumbnail of Benzo(a)pyrene metabolism by lymphocytes from normal individuals and individuals carrying the mediterranean variant of glucose-6-phosphate dehydrogenase

International Journal of Cancer, 1987

In vitro growing human lymphocytes (HL) and fibroblasts, isolated from glucose-6-phosphate dehydr... more In vitro growing human lymphocytes (HL) and fibroblasts, isolated from glucose-6-phosphate dehydrogenase (G6PD).de. ficient subjects (Mediterranean variant), show a sharp decrease in this enzymatic activity and in NADPH:NADP+ ratio. These cells are less able than controls to hydroxylate benzo(a)pyrene (BaP) when tested in the absence of an exogenous NADPH-generating system. They exhibit great resistance to the toxic effect of BaP. G6PD-deficient fibroblasts are less prone than controls to in vitro transformation by BaP. To investigate whether this depends on a decreased production of active BaP metabolites and 6aP:DNA adducts by G6PD-deficient cells, BaP metabolism was studied in G6PDdeficient HL cultured in vitro in the presence of mitogens and treated with BaP for 24 hr. HPLC profiles of organo-and water-soluble metabolites revealed that both types of benzo(a)anthracene (6aA)-induced HL produced: 4,5-, 7.8-, 9,IO-diols. l,3-, 3,6-quinones, 3-, 9-hydroxy and 2 peaks of more polar metabolites. There was a 25-76% decrease of organoand water-soluble metabolites in the G6PD-deficient cells. When H L were incubated with 7,8-diol, the formation of metabolites mutagenic for Salmonella typhimurium (His-) was very low in G6PD-deficient cells. 6aP:deoxyadenosine (dAde) and BaPdeoxyaguanosine (dGua) adducts were identified after incubation of both types of HL with BaP. There was a 31.79% fall in adduct formation by G6PD-deficient cells. Our results indicate that G6PD-deficient human lymphocytes are less able to metabolize BaP than normal lymphocytes. We suggest that the NADPH pool is inadequate, in deficient cells, for active BaP metabolism.

Research paper thumbnail of Effect of a cholesterol-rich diet on cholesterol content and phagocytic activity of rat macrophages

Agents and Actions, 1976

Treatment for 11-13 weeks with a cholesterol-rich diet induced increases in free and esterified s... more Treatment for 11-13 weeks with a cholesterol-rich diet induced increases in free and esterified serum cholesterol. There was also an increase in free cholesterol of peritoneal macrophages. A 2.2 times rise in the cholesterol to phospholipid ratio of plasma membranes occurred in cholesterol-enriched macrophages. No changes were observed in phagolysosomes. Cholesterol-enriched macrophages showed a 35.8% inhibition of latex particles phagocytosis. When lipid droplets were substituted for latex the inhibition was 81.7%.

Research paper thumbnail of Phenobarbital stimulation of cytochrome P-450 and aminopyrine N-demethylase in hyperplastic liver nodules during LD-ethionine carcinogenesis

Cancer Letters, 1978

Microsomes isolated from hyperplastic liver nodules and hepatomas, induced by DL-ethionine, exhib... more Microsomes isolated from hyperplastic liver nodules and hepatomas, induced by DL-ethionine, exhibited a reduced cytochrome P-450 content and aminopyrine N-demethylase activity when compared to the organelles of control and surrounding non-nodular liver. Phenobarbital administration to rats caused an increase of microsomal protein, cytochrome P-450 and aminopyrine N-demethylase in all tissue tested. In the hepatoma the rise of cytochrome P-450 and aminopyrine N-demethylase/g of tissue was very low and it is compensated by a slight increase of microsomal protein. In hyperplastic nodules as well as in control and surrounding livers, cytochrome P-450 and aminopyrine N-demethylase increased more than microsomal protein. However, the phenobarbital-induced stimulation was significantly lower in hyperplastic nodules than in control and surrounding livers.

Research paper thumbnail of Effect of cholesterol content on some physical and functional properties of mitochondria isolated from adult rat liver, fetal liver, cholesterol-enriched liver and hepatomas AH-130, 3924A and 5123

Biochimica et Biophysica Acta (BBA) - Biomembranes, 1975

The cholesterol to phospholipid ratio in mitochondria from hepatomas AH-130, 3924A and 5123 is hi... more The cholesterol to phospholipid ratio in mitochondria from hepatomas AH-130, 3924A and 5123 is higher than in the particles isolated from adult or fetal rat livers. Nearly all the cholesterol of hepatoma mitochondria is located in membranes. As in liver mitochondria, in the particles isolated from hepatoma AH-130 there is more cholesterol in the outer than in the inner membrane. In mitochondria from cholesterol-enriched liver and hepatomas, there occurs a decrease in extent of hypoosmotic and phosphate-induced swelling and a decrease of conformational changes linked to energy states. The phenomenon is more marked in particles which exhibit higher cholesterol to phospholipid ratios. A statistically significant negative correlation exists between the cholesterol to phospholipid ratio and extent of volume or conformational changes. No significant modifications of these parameters were found in fetal liver mitochondria. Cholesterol content does not influence K+ uptake by cholesterol-enriched or hepatoma mitochondria. Nor does cholesterol content affect the respiratory increment related to this uptake. As a consequence of K+ uptake, total mitochondrial water exchangeable with tritiated water rises 20% while sucrose-impermeable water rises 42-48% in both adult rat liver and hepatoma AH-130 mitochondria. Absorbance changes linked to ion uptake do not correspond merely to variations in mitochondrial water content. Water content is apparently not influenced by the cholesterol to phospholipid ratio. However, the ratio is significantly correlated to both extent and initial rate of absorbance decrease of mitochondrial suspensions during K+ uptake. The higher the ratio, the lower the extent and initial rate of absorbance decrease.