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Biomedical subjects

M Grilli

Publications and source records attributed to M Grilli.

At least 37 records · Page 2Linked to original sources
PubMed1997

Regulation of mouse neuropeptide Y Y1 receptor gene transcription: a potential role for nuclear factor-kappa B/Rel proteins.

We previously isolated a 1.3-kb genomic fragment in the 5'-flanking region of the murine neuropeptide Y (NPY) Y1 receptor gene, which is able to drive the expression of LacZ reporter gene in neuronal cells. We determined the ability of deletion mutants of this region to modulate transcription of the heterologous luciferase gene in the Y1 receptor-expressing neuroblastoma/ glioma NG108-15 cells and the Y1 receptor-deficient 293 cells. Results suggest the presence of a cell type-specific core promoter (-399 to -218 from the initiator ATG) and, upstream, of two positive and two negative regulatory elements. Sequence analysis of the Y1 receptor promoter identified two decameric sequences corresponding to consensus binding sites for nuclear factor-kappa B/Rel proteins. Gel shift analysis indicated that a 29-bp oligonucleotide comprising the two putative kappa B sites, which we refer to as Y1-kappa B sequence, specifically binds kappa B-related complexes in nuclear extracts from rat brain areas, NG108-15 cells, and the murine T cell clone A.E7. In nuclear extracts from A.E7 and NG108-15 cells, the Y1-kappa B sequence specifically binds an additional complex whose molecular nature remains to be elucidated. Through transient transfection studies, we also demonstrated that the Y1-kappa B sequence acts as an enhancer element, inferring its potential role in regulation of the Y1 receptor gene expression.

Animals↗
PubMed1996

Neuroprotection by aspirin and sodium salicylate through blockade of NF-kappaB activation.

Aspirin (acetylsalicylic acid) is a commonly prescribed drug with a wide pharmacological spectrum. At concentrations compatible with amounts in plasma during chronic anti-inflammatory therapy, acetylsalicylic acid and its metabolite sodium salicylate were found to be protective against neurotoxicity elicited by the excitatory amino acid glutamate in rat primary neuronal cultures and hippocampal slices. The site of action of the drugs appeared to be downstream of glutamate receptors and to involve specific inhibition of glutamate-mediated induction of nuclear factor kappa B. These results may contribute to the emerging theme of anti-inflammatory drugs and neurodegeneration.

Animals↗
PubMed1996

Interleukin-1beta and glutamate activate the NF-kappaB/Rel binding site from the regulatory region of the amyloid precursor protein gene in primary neuronal cultures.

We originally reported that members of the family of transcription factors NF-kappaB/Rel can specifically recognize two identical sequences, referred to as APPkappaB sites, which are present in the 5'-regulatory region of the APP gene. Here we show that the APPkappaB sites interact specifically with a complex which contains one of the subunits of the family, defined as p50 protein, and that they act as positive modulators of gene transcription in cells of neural origin. Additionally, the nuclear complex specifically binding to the APPkappaB sites is constitutively expressed in primary neurons from rat cerebellum and it is up-regulated in response to both the inflammatory cytokine interleukin-1beta (IL-1beta) and the excitatory amino acid glutamate. Since IL-1, whose levels are known to be induced in brain of individuals affected by Alzheimer's disease, and glutamate, are stimuli which have been regarded as major actors on the stage of neurodegenerative processes, we believe our evidence as potentially relevant for understanding the neuropathology associated with Alzheimer's disease.

Alzheimer Disease↗
PubMed1996

Plasma lipoprotein(a) levels in subjects attending a metabolic ward. Discrimination between individuals with and without a history of ischemic stroke.

In this cross-sectional study we compared the abilities of lipoprotein(a) [Lp(a)], plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator (TPA) to discriminate between individuals with and without a history of stroke from among subjects in a metabolic ward. A total of 210 subjects (108 men and 102 women; mean age, 63.8 years; range, 31 to 86 years) provided plasma and DNA samples for the study. Of these, 51 men and 50 women had a history of ischemic stroke. The 109 subjects without a history of stroke were compared with those with such a history for major risk factors for ischemic events. Mean plasma TPA and PAI-1 levels significantly (P < .001) discriminated among subjects younger than 70 years with a history of stroke. The mean plasma Lp(a) level of stroke subjects (21.9 mg/dL) did not differ significantly from that of control subjects (15.2 mg/dL). However, among individuals < 70 years old, Lp(a) plasma levels > 50 mg/dL were more common among stroke patients (8 with versus 1 without, P < .01 by chi 2 test). A molecular variation in the 5' flanking region of the apo(a) gene that has been related to elevated Lp(a) plasma levels (G/A-914) was not strongly correlated with circulating levels of Lp(a), nor did Lp(a) levels correlate with a polymorphism of the apo(a) gene (G/A-21), which is strongly linked (P < .001) to the G/A-914 variation. In this setting, the relation between Lp(a) and cerebral ischemia appears to be limited to individuals below 70 years with elevated (> 50 mg/dL) plasma levels of the lipoprotein.

Adult↗
PubMed1995

Identification and characterization of a kappa B/Rel binding site in the regulatory region of the amyloid precursor protein gene.

Several observations support the hypothesis that pathogenetic mechanisms of beta amyloid formation in Alzheimer's disease may involve alterations in amyloid precursor protein (APP) gene expression. In this regard, molecular dissection of the APP gene transcriptional regulation is of primary importance. We report evidence that members of the family of transcription factors NF kappa B/Rel can specifically recognize two identical sequences located in the 5'-regulatory region of APP. These sequences, which we refer to as APP kappa B sites, interact preferentially with p50-containing members of the family. In particular, p50 homodimers and p50/p65 and p50/c-Rel heterodimers act as transcriptional activators at the APP kappa B site. Finally, the nuclear complex specifically binding to the APP kappa B sites proves to be an integral part of neurons and lymphocytes.

Alzheimer Disease↗
PubMed1995

Opposing regulation of amyloid precursor protein by ionotropic and metabotropic glutamate receptors.

The effects of the ionotropic glutamate receptor (iGluR) selective agonist N-methyl-D-aspartate (NMDA) on amyloid precursor protein (APP) levels were investigated in primary cultures of rat cerebellar granule cells. Both immunocytochemistry and immunoblotting techniques showed increased APP levels 4 h after a 15 min pulse with NMDA. This effect was completely prevented by incubating the neurones in the presence of the selective metabotropic GluR (mGluR) agonist 1S,3R-ACPD. This phenomenon was related, in terms of doses and time, with the observed 1S,3R-ACPD-mediated protection on NMDA-induced granule cell death. Our findings indicate that APP metabolism is differentially regulated by the stimulation of various GluR subtypes. The GluR-mediated changes in APP content might participate in the control of neuronal viability.

Amyloid beta-Protein Precursor↗
PubMed1995

Raised plasma fibrinogen concentrations in subjects attending a metabolic ward--relation to family history and vascular risk factors.

We have evaluated plasma fibrinogen levels in 171 subjects attending a metabolic ward. As in the general population, a significant difference in plasma fibrinogen concentrations (p < 0.05) was found between subjects with diabetes mellitus or hypertension and those without. However, fibrinogen was also abnormally high (p < 0.05) when evaluated according to the presence of a family history of ischemic complications of atherosclerosis (p < 0.05). In this setting, fibrinogen correlated with diabetes mellitus or hypertension as well as with familial risk, and the latter interacted with hypertension (p < 0.05) in accounting for plasma fibrinogen. The relationships between certain fibrinogen genotypes and familial risk have then been evaluated. Analysis of a locus (1.3 kb, HAE III digestion) of the promoter region of the B beta fibrinogen gene, identified a polymorphic cutting site. The allele with the alternative restriction site (H1) was associated with mean fibrinogen levels which were 0.1-0.3 g/l lower than those associated with the other allele (H2). This difference was not statistically significant. No obvious association was found between the familial risk and the presence of the H2 allele. We conclude that in a group of subjects from a metabolic ward, a positive family history for ischemic complications of atherosclerosis is consistently associated with high plasma fibrinogen levels. Interaction with hypertension significantly strengthens the association.

Adult↗
PubMed1995

Metoclopramide blocks bromocriptine induced antihypertensive effect in hypertensive patients.

Two groups of patients with essential hypertension were studied at the Vargas Hospital of Caracas. The first group of 9 patients under placebo treatment for 1 week received a single 2.5 mg oral dose of bromocriptine. Cardiovascular and biochemical parameters including arterial pressure, heart rate, plasma renin activity, and plasma aldosterone levels were evaluated during the 6-hour period before and after the administration of drugs. The second experimental design was as follows: 9 patients received 30 mg metoclopramide daily (divided in 3 doses) for 1 week. At the end of the period a single oral dose of 2.5 mg of bromocriptine was given to each patient. The cardiovascular and biochemical parameters were also determined. Bromocriptine reduced both systolic and diastolic arterial pressure. The peak antihypertensive effect was shown 3 hours after administration of the drug, but the reduction of arterial pressure lasted approximately 6 hours. At the same time bromocriptine reduced plasma aldosterone levels and plasma renin activity. This reduction persisted 6 hours after its administration. Metoclopramide reversed the antihypertensive effect of bromocriptine and its effect on aldosterone secretion and plasma renin activity. We conclude from these findings that bromocriptine acts as an antihypertensive agent by stimulating DA2 dopaminergic receptor, the dopaminergic receptor involved in aldosterone and renin secretion is possibly DA2.

Aldosterone↗