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Biomedical subjects

M P Russo

Publications and source records attributed to M P Russo.

12 recordsLinked to original sources
PubMed2001

Regulatory role of phosphatidylinositol 3-kinase on TNF-alpha-induced cyclooxygenase 2 expression in colonic epithelial cells.

BACKGROUND AND AIMS: Cyclooxygenase (COX)-2 is up-regulated in most colonic cancers and in inflammatory bowel disease in which tumor necrosis factor (TNF)-alpha is believed to play a central role. There has been recent speculation on the activation of phosphatidylinositol 3-kinase (PI 3-kinase) by TNF-alpha and its role in the regulation of genes controlled by NF-kappaB. We investigated the regulatory role of PI 3-kinase on COX-2 expression in colonic epithelial cells. METHODS: In HT-29 and Caco-2 colonic epithelial cells, COX-2 expression was induced by either TNF-alpha or interleukin (IL)-1alpha as observed by Northern and Western analyses. COX-2 activity was assessed by measuring prostaglandin E(2) (PGE2) production by enzyme-linked immunosorbent assay. NF-kappaB binding activity was assessed by electrophoretic mobility shift assay. PI 3-kinase activity was measured by quantifying the accumulation of PI 3-kinase-dependent D-3 lipid products by high-performance liquid chromatography. RESULTS: The PI 3-kinase inhibitor wortmannin up-regulated induced COX-2 expression in a concentration-dependent manner in both HT-29 and Caco-2 cells. An alternative PI 3-kinase inhibitor, LY294002, caused up-regulation of induced COX-2 messenger RNA (mRNA) in HT-29 cells at concentrations of < or =1 micromol/L. IL-4 and IL-13, which are known to activate PI 3-kinase, down-regulated HT-29 COX-2 mRNA, protein, and PGE2 production. NF-kappaB binding activity was unaltered by PI 3-kinase inhibition in HT-29 cells, in which TNF-alpha was shown to activate PI 3-kinase directly. CONCLUSIONS: COX-2 is negatively regulated by PI 3-kinase; we propose that the inhibitory effect of IL-4 and IL-13 is mediated via a PI 3-kinase-dependent pathway. This mechanism does not appear to involve NF-kappaB because PI 3-kinase inhibition did not alter NF-kappaB binding activity. TNF-alpha can activate PI 3-kinase directly in addition to inducing COX-2.

Androstadienes↗
PubMed1999

Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity.

NF-kappa B plays a critical role in the transcriptional regulation of proinflammatory gene expression in various cells. Cytokine-mediated activation of NF-kappa B requires activation of various kinases, which ultimately leads to the phosphorylation and degradation of I kappa B, the NF-kappa B cytoplasmic inhibitor. The food derivative curcumin has been shown to inhibit NF-kappa B activity in some cell types. In this report we investigate the mechanism of action of curcumin on cytokine-induced proinflammatory gene expression using intestinal epithelial cells (IEC). Curcumin inhibited IL-1 beta-mediated ICAM-1 and IL-8 gene expression in IEC-6, HT-29, and Caco-2 cells. Cytokine-induced NF-kappa B DNA binding activity, RelA nuclear translocation, I kappa B alpha degradation, I kappa B serine 32 phosphorylation, and I kappa B kinase (IKK) activity were blocked by curcumin treatment. Wound-induced p38 phosphorylation was not inhibited by curcumin treatment. In addition, mitogen-activated protein kinase/ERK kinase kinase-1-induced IL-8 gene expression and 12-O-tetraphorbol 12-myristate 13-acetate-responsive element-driven luciferase expression were inhibited by curcumin. However, I kappa B alpha degradation induced by ectopically expressed NF-kappa B-inducing kinase or IKK was not inhibited by curcumin treatment. Therefore, curcumin blocks a signal upstream of NF-kappa B-inducing kinase and IKK. We conclude that curcumin potently inhibits cytokine-mediated NF-kappa B activation by blocking a signal leading to IKK activity.

Animals↗
PubMed1998

Interleukin-15 (IL-15) induces NF-kappaB activation and IL-8 production in human neutrophils.

Interleukin-2 (IL-2) and IL-15 exert similar biological actions, which largely reflect the fact that their receptors share common beta and gamma subunits; in contrast, distinct subunits are required for high-affinity binding of either cytokine to a heterotrimeric receptor complex. Human neutrophils are known to express both the beta and gamma subunits of the IL-2/IL-15 receptor complex, and we now report that they also constitutively express messenger RNA transcripts encoding the IL-15 receptor chain, suggesting that they possess functional, heterotrimeric IL-15 receptors. Accordingly, we show that in neutrophils, IL-15 elicits several functional responses. In particular, neutrophils synthesize and release IL-8 in response to IL-15, but not to IL-2. Moreover, a nuclear factor-kappaB (NF-kappaB) DNA-binding activity was enhanced in nuclear extracts of IL-15-treated neutrophils, which could be supershifted by antibodies to p50 or RelA. Again, no detectable effect of IL-2 was observed on this response. In peripheral blood lymphocytes (PBL), however, both IL-2 and IL-15 were potent inducers of NF-kappaB activation. Conversely, neither IL-15 nor IL-2 elicited the formation of activator protein-1 (AP-1) DNA-binding complexes in neutrophils, even though both cytokines were found to activate these DNA-binding activities in PBL. Collectively, these observations establish neutrophils as a useful cellular model to discriminate between the actions of IL-15 and IL-2. More importantly, this is the first demonstration that IL-15 has the ability to induce NF-kappaB and AP-1 activation, which further emphasizes the potential relevance of this newly discovered cytokine to immune and inflammatory processes.

Gene Expression↗
PubMed1997

Identification of a double mutation (D160V-K161E) in the p67phox gene of a chronic granulomatous disease patient.

In neutrophils of a chronic granulomatous disease (CGD) patient with a lack of p67phox the mRNA for p67phox was present in normal amount and size. This mRNA was reverse transcribed, and the coding region was analyzed by single-strand conformation polymorphism analysis. Direct DNA sequencing allowed the identification of a A479-to-T and A481-to-G substitution in exon 5 of the p67phox gene resulting in a double nonconservative amino acid change 160Lys-to-Glu and 161Asp-to-Val (D160V-K161E). This defect was found in the genomic DNA of this patient in heterozygous state and does not correspond to those previously found in other cases of CGD lacking the p67phox.

Genes↗
PubMed1995

Analysis of linkage disequilibrium between different cystic fibrosis mutations and three intragenic microsatellites in the Italian population.

Three intragenic microsatellites of the CFTR gene, a TA and a CA repeats, namely IVS17bTA and IVS17bCA, located in intron 17b and a CA repeat (IVS8CA) located in intron 8 of the CFTR gene, were analyzed in a large sample of Italian cystic fibrosis (CF) and normal chromosomes. Linkage disequilibrium was evaluated between each marker and difference CF mutations on a total of 377 CF and 358 normal chromosomes. Our results are consistent with the hypothesis that all delta F508 chromosomes derive from a single mutational event. The same hypothesis is valid for mutations G542X, N1303K, 1717-1G-->A, which might have been originated more recently than delta F508.

Cystic Fibrosis↗
PubMed1995

Regulation of GRO alpha production in human granulocytes.

GRO alpha, a member of the chemokine superfamily, exerts potent stimulatory actions on granulocytes. In this report, we show that activated human polymorphonuclear leukocytes (PMN) are able to produce significant amounts of GRO alpha. Lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF alpha), and yeast particles opsonized with IgG (Y-IgG) had the ability to induce GRO alpha release, with Y-IgG being the most potent stimulus. The extracellular production of GRO alpha was also modulated by both interferon-gamma (IFN gamma) and interleukin-10 (IL-10). IFN gamma significantly inhibited the production of GRO alpha by PMN stimulated for 2 hr with LPS, TNF alpha, or Y-IgG, but potentiated the production of GRO alpha in cells stimulated for 18 hr with LPS and TNF alpha. IL-10 moderately suppressed the Y-IgG-induced production of GRO alpha, but strongly inhibited the action of LPS and potentiated the effect of TNF alpha. As revealed by Northern blot analysis, the extracellular production of GRO alpha under the experimental conditions used did not always correlate with parallel changes at the level GRO alpha mRNA expression, suggesting that production of GRO alpha by PMN might be regulated at post-transcriptional, translational, or post-translational level. These findings identify a novel biological function of PMN, likely involved in the modulation of the acute inflammatory response.

Chemokine CXCL1↗
PubMed1994

Informativity of intragenic microsatellites for carrier detection and prenatal diagnosis of cystic fibrosis in the Italian population.

Molecular diagnosis of cystic fibrosis (CF) in the Italian population, based on the detection of the deltaF508 mutation (51.2% of CF chromosomes), provides full informativity for prenatal diagnosis (PDN) in about 28% of families at risk. Identification of the predominant non-deltaF508 mutations allows the characterization of about 70% of CF chromosomes, making approximately 48% of couples fully informative. In families where at least one chromosome remains uncharacterized, allele segregation is still determined using RFLPs closely linked to the CF gene. The recent identification of three polymorphic clusters of dinucleotide repeats (IVS8/GT, IVS17b/TA and IVS17b/CA) led us to evaluate whether their analysis might improve feasibility studies for prenatal diagnosis or heterozygote identification. One hundred nuclear families with a CF child, reflecting the general Italian deltaF508 mutation distribution, were genotyped for the three microsatellites. In this study microsatellite analysis using IVS8/GT and IVS17b/TA allowed the identification of both parental CF chromosomes in 94% of couples; inclusion in the study of the less polymorphic repeat locus, IVS17b/CA, slightly improved this percentage (97%). Hence, a strategy involving primarily the detection of the deltaF508 mutation and secondarily microsatellite analysis makes possible PDN of CF in virtually all Italian CF families.

Base Sequence↗
PubMed1992

Four new mutations of the CFTR gene (541delC, R347H, R352Q, E585X) detected by DGGE analysis in Italian CF patients, associated with different clinical phenotypes.

The delta 508 mutation accounts for about 53% of the molecular defects causing cystic fibrosis (CF) in Italy. The numerous additional mutations detected so far are all relatively rare, and about 30% of CF chromosomes carries unknown mutations in our patients. In order to identify the non-delta F508 mutations causing CF in our population, we performed GC-clamped denaturing gradient gel electrophoresis (DGGE) on 9 exons of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in a sample of 86 Italian CF patients carrying unknown mutations on at least one chromosome. Direct sequencing of 17 samples showing an altered electrophoretic mobility allowed the identification of four new mutations (541delC, R347H, R352Q, and E585X), five mutations already known (G85E, I148T, G178R, 1078delT, and R347P), and one rare variant (1898 + 3A-->G). The strategy based on GC-clamped DGGE represents an efficient and rapid approach for mutation detection for those genetic diseases, such as CF, in which a large number of rare molecular defects has been described.

Base Sequence↗
PubMed1985

Lipid bound sialic acid in cancer patients.

Serum lipid-bound sialic acid (LSA) was measured with a recently described procedure in 108 healthy subjects and in 138 patients with a variety of solid tumors and hematologic malignancies. At the time of serum sampling, 128 patients had active disease and 10 patients had no evidence of disease. LSA was elevated in 104 of 128 (81.2%) patients with active disease, while carcinoembryonic antigen, analyzed in 74, was elevated only in 21 (28.4%) (P less than 0.05). Sensitivity of the serum LSA test ranged from 66% for breast and gastrointestinal cancer to 92% for lung cancer. In patients with lung cancer, ovarian cancer or Hodgkin's disease, LSA was correlated with the extent of disease and it also proved to be useful in following the course of disease. Our preliminary data indicate that this test can be used as a monitor of tumor burden.

Breast Neoplasms↗
PubMed1983

Relationship between Grade III placentas and biparietal diameter determinations.

Grade III placentas were found in 133 (12 per cent) of 1,082 pregnant women evaluated ultrasonographically after 20 weeks of gestation. Associated biparietal diameter measurements ranged from 7.2 to 10 cm. In 11 women with no complications known to accelerate fetal lung maturity or to induce premature placental maturation, grade III placentas were observed between 30 and 33 weeks of gestation. Gestational ages determined according to the growth adjusted sonographic age method of Sabbagha were accurate within one to three days. Considering the risk of hyaline membrane disease at those gestational ages, a grade III placenta cannot be equated with fetal lung maturity. Criteria other than placental grading should be used to assess the pulmonary status of the fetus.

Female↗