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Biomedical subjects

B Costa

Publications and source records attributed to B Costa.

At least 19 recordsLinked to original sources
PubMed2006

The non-psychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells.

Recently, we have shown that the non-psychoactive cannabinoid compound cannabidiol (CBD) induces apoptosis of glioma cells in vitro and tumor regression in vivo. The present study investigated a possible involvement of caspase activation and reactive oxygen species (ROS) induction in the apoptotic effect of CBD. CBD produced a gradual, time-dependent activation of caspase-3, which preceded the appearance of apoptotic death. In addiction, release of cytochrome c and caspase-9 and caspase-8 activation were detected. The exposure to CBD caused in glioma cells an early production of ROS, depletion of intracellular glutathione and increase activity of glutathione reductase and glutathione peroxidase enzymes. Under the same experimental condition, CBD did not impair primary glia. Thus, we found a different sensitivity to the anti-proliferative effect of CBD in human glioma cells and non-transformed cells that appears closely related to a selective ability of CBD in inducing ROS production and caspase activation in tumor cells.

Cannabidiol↗
PubMed2005

[The Framingham function overestimates stroke risk for diabetes and metabolic syndrome among Spanish population].

OBJECTIVE: To estimate stroke risk for diabetes, isolated or associated to metabolic syndrome (MS) according WHO and National Cholesterol Education Program (NCEP) criteria. DESIGN: Multicentre and prospective cohort study. SETTING: Primary health care. PARTICIPANTS: Subjects between 55-85 years-old without any evidence of stroke, included from 1998 in a random population sample for MS follow-up during routine practice in Reus (Tarragona, Spain). MAIN MEASUREMENTS: Stroke risk was achieved using Framingham function by means of a computerized algorithm using a diagnostic factorial design (diabetes and/or MS). Theoretical stroke risk and cumulated incidence of stroke events (1998-2003) were compared. RESULTS: Among 728 subjects (412 women, mean age =66 years old, body mass index =29 kg/m2), 457 (62.8%) did not have diabetes, nor MS, 93 (12.8%) had MS without diabetes, 72 (9.9%) diabetes without MS, and 106 (14.5%) presented both conditions (WHO rules). According NCEP criteria were 60.7%, 14.8%, 7.8%, and 16.7%, respectively. Ten-year estimated stroke risk accounted for (WHO/NCEP) 8.4/9.1%, 10.8/10.5%, 18/17.3%, and 18.8/19.1%. Cumulated incidence for stroke events were: 2.8%, 1.4%, 5.4%, and 3.8% (WHO), and 2.5%, 2.8%, 3.5%, and 5.8%, respectively (NCEP). CONCLUSIONS: Stroke risk scores were extremely increased among diabetic subjects irrespective to MS diagnose. The Framingham function probably overestimates stroke risk among Spanish individuals.

Diabetes Mellitus, Type 2↗
PubMed2005

[The RECORD project. continuous blood glucose monitoring among high risk subjects for developing diabetes in Spanish primary health care].

OBJECTIVE: To evaluate the accuracy of continuous blood glucose monitoring (CBGM) in order to asses diagnostic procedures and predict glycaemic status in type 2 prediabetes. DESIGN: Observational, multicenter, cross-sectional (phase 1) plus longitudinal, cohort follow-up study (phase 2). SETTING: Five primary health-care centers. INTERVENTIONS: A total of 84 high-risk subjects will be included after a non-diabetic oral glucose tolerance test (OGTT). A first CBGM using a subcutaneous microdialysis glucose sensor technique in order to obtain a continuous profile will be carried out. Two different cohorts, subjects with normal OGTT (n = 42) and individuals with prediabetic hyperglycemia (n = 42) will be established. Diagnoses will be revised at 12 and 24 month follow-up by means of an OGTT together with a new monitoring. MAIN MEASUREMENT: Demographical, clinical (including metabolic syndrome items), basic, and advanced analyses (inflammation emergent markers, insulinemia, C-peptide). CBGM computerized analysis comparing fasting, preprandial, postprandial, nocturnal period, and area under the curve of continuous profile with regular diagnoses, taking into account temporary concordance. Relationship of CBGM parameters with normal glucose tolerance or diabetes incidence. Evaluation of day-to-day quality of life of CBGM users by means of an standardized Likert questionnaire. DISCUSSION: This study seeks to demonstrate the effectiveness and feasibility of CBGM, more physiological than OGTT and based on an underestimated random blood glucose diagnostic criterion. This innovative system may provide interesting scientific data in the field of type 2 prediabetes.

Blood Glucose↗
PubMed2005

Comparison of liquid based cytology and histology for the evaluation of HER-2 status using immunostaining and CISH in breast carcinoma.

BACKGROUND: HER-2 amplification is an important prognostic biomarker and treatment determinant in breast carcinoma. AIMS: To correlate immunocytochemical (ICC) expression of HER-2 and gene amplification determined by chromogenic in situ hybridisation (CISH) using liquid based cytology (LBC) with immunohistochemistry (IHC) and CISH using histological samples of the same breast carcinomas. METHODS: Frozen sections and cytobrushings of 103 breast carcinomas were analysed. Four techniques were performed on each tumour: two on LBC samples (ICC, and CISH, both graded as positive, indeterminate, or negative) and two on histological samples (IHC and CISH). Two cell lines (MCF-7, negative; BT 474, positive) were used as controls for cytological analysis. A complementary fluorescence in situ hybridisation technique was carried out in histological samples with low amplification (4-10 dots/nucleus). RESULTS: Interobserver agreement for the four techniques calculated by the kappa coefficient indicated a substantial agreement. Nine cases failed in cytology because of poor cellularity. Among 94 cases, 19 were amplified; 73, 12, and 9 tumours were scored 0 or 1+, 2+, and 3+, respectively by IHC and 75, 13, and 6, respectively, by ICC. CISH found no amplification in 72 tumours. Correlations between the IHC and CISH results in the histological and cytological samples were always significant. CONCLUSIONS: Her-2 status could be determined in LBC samples and correlated well with reference histological methods using in situ hybridisation. ICC was less reliable because of the presence of the cytoplasmic membrane. However, these results should be confirmed by a large multicentre study.

Adult↗
PubMed2004

Peripheral type benzodiazepine receptor in human parathyroid glands: up-regulation in adenoma.

In this study we report the presence of peripheral benzodiazepine receptors (PBRs) in human parathyroid glands and describe the effect of their benzodiazepine type ligands on parathyroid cell function. PBR binding features in normal parathyroid tissue were characterized and compared to parathyroid adenoma, using a specific and selective ligand for PBR, [3H] 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinoline-carboxamide ([3H]PK11195). Affinity and density of [3H]PK11195 binding sites in homogenate membrane preparations from adenomatous and normal tissues were determined. Parathyroid adenoma showed a statistically significant 2.2 fold increase of [3H]PK11195 binding sites, while the affinity remained unchanged. Our results represent the first evidence of PBRs in parathyroid glands and suggest for them a role in influencing PTH release. A clear trend of PBR up-regulation in parathyroid adenoma was also found.

Adenoma↗
PubMed2003

Repeated treatment with the synthetic cannabinoid WIN 55,212-2 reduces both hyperalgesia and production of pronociceptive mediators in a rat model of neuropathic pain.

The antinociceptive properties of cannabinoids in persistent pain are not fully elucidated. We investigated the effect of repeated treatment with the synthetic cannabinoid receptor agonist WIN 55,212-2 on the neuropathic pain induced in rats by chronic constriction of the sciatic nerve. WIN 55,212-2 administered daily throughout the development of neuropathy reversed the hyperalgesia, at a dose (0.1 mg x kg(-1), s.c.) that had no effect on the nociceptive responses of either paw contralateral to the sciatic ligation or of animals subjected to sham surgery. At 14 days after injury, the levels of mediators known to be involved in neuropathic pain, such as prostaglandin E2, NO and the neuronal NOS, were increased. Repeated treatment with WIN 55,212-2 abolished these increases. In the light of the current clinical need for neuropathic pain treatments, these findings indicate that cannabinoid agonists, at doses devoid of psychoactive effects, could constitute important compounds for the development of new analgesics.

Analgesics↗
PubMed2003

Effects of fluoride and aluminum from ionomeric materials on S. mutans biofilm.

Ionomeric materials release different proportions of fluoride and aluminum. Their simultaneous effect on the acidogenicity and composition of S. mutans biofilm is unknown. Six cylindrical specimens of each material (Ketac-fil, Vitremer, Fuji-Ortho LC, F-2000, and Z-100) were incubated with S. mutans GS-5 in culture media containing 5% sucrose (w/v). The media were changed daily for seven days, during which the pH and concentrations of fluoride and aluminum were determined. Furthermore, the concentrations of these ions and insoluble polysaccharide were determined in the biofilm formed at the end of the experimental period. The results showed that all the materials tested released fluoride. However, Vitremer released the highest amount of aluminum and was the most effective in reducing the acidogenicity of S. mutans biofilms. It also significantly affected both biofilm formation and composition. Thus, this study suggests that aluminum released by ionomeric materials may enhance the biological effects of fluoride.

Acrylic Resins↗
PubMed2002

[Cardiovascular risk and glucose metabolism: agreements and discrepancies between the WHO-85 and ADA-97 classifications].

UNLABELLED: AIM. To identify the differences between coronary heart disease risk in patients with altered basal glucemia (ABG), oral glucose intolerance (OGI) and type II diabetes mellitus according to the WHO-85 and ADA-97 diagnostic classifications, in an adult population at high risk for diabetes mellitus. DESIGN: Descriptive, cross-sectional, multicenter study.Setting. Seven primary health care centers in Spain.Patient. 970 persons considered the population at risk for type II diabetes mellitus. MEASURES: Participants were classified according to the criteria of the WHO-85 (normal, OGI, diabetes) and the ADA-97 system (normal, ABG, diabetes). The following variables were recorded: age, sex, smoking habit, body mass index, systolic blood pressure, diastolic blood pressure, basal glucemia, glucemia 2 h after an oral glucose tolerance test, HbA1c, microalbmuniuria, total cholesterol, HDL, LDL and triglycerides. Coronary heart disease risk was calculated with the 1998 table developed by Wilson et al. on the basis of the Framingham study. RESULTS: A total of 970 participants were studied. Mean age was 58.6 #+ 12.4 years; 453 were men (46.7%) and 517 were women (53.3%). Our analysis showed that cardiovascular disease risk factors were less frequent in normal subjects, and that their prevalence was higher in persons with diabetes (according to both WHO and ADA classifications). There were no significant differences in coronary heart disease risk or different risk factors between analogous groups in the two classification systems (normal, OGI/ABG or diabetes). Coronary heart disease risk in persons with different types of alterations in glucose metabolism was 11.3% in normal subjects, 14% in persons with OGI and 27.3% in persons with diabetes according to the WHO-85 system, and 11.4% in normal subjects, 15.7% in persons with ABG and 29.5% in persons with diabetes according to the ADA-97 system. CONCLUSIONS: The greater the alteration in carbohydrate metabolism, the greater the coexistence of risk factors and the estimated risk of coronary heart disease. There were no significant differences in the presence of cardiovascular risk factors, or in the relationship between carbohydrate metabolism and coronary heart disease risk, between analogous stages identified with one classification system or the other.

Blood Glucose↗
PubMed2002

In vitro cytotoxic effect of bread wheat gliadin on the LoVo human adenocarcinoma cell line.

The pathogenesis of celiac disease is not completely understood but, although the initial step of the process is still unclear, an altered immune response seems to play a major role. Previous studies of the biological properties of gliadin have highlighted its cytotoxic effects, and the aim of this study was to develop an in vitro technique to study them. The LoVo (human colon adenocarcinoma) cell line grown in two-dimensional cultures was exposed to different concentrations of digested bread wheat gliadin (62, 125, 250, 500 and 750 microg/ml) for 48 h, after which cell growth and oxidative balance (the content of reduced glutathione (GSH), and peroxidase, transferase and reductase activity) was evaluated. Other food proteins were used as controls. Our data revealed a statistically significant inhibition of cell growth in proportion to the gliadin concentration (from 26 to 100%), combined with a decrease in GSH content (-38% at 500 microg/ml) and reduced enzymatic activity (-30% at 500 microg/ml). The controls did not show any noxious effect. Our results confirm the usefulness of LoVo cells in evaluating gliadin cytotoxicity and that they can be used to investigate the biological properties of gliadin.

Adenocarcinoma↗
PubMed2002

[Value of pulsed Doppler tissue imaging for early detection of myocardial dysfunction with anthracyclines].

The cumulative and definitive nature of chronic cardiotoxicity of anthracyclines requires a preventive strategy of early diagnosis. The authors undertook a prospective study of the association of echocardiography, mitral Doppler and pulsed Doppler tissue imaging of the left ventricular lateral and posterior walls in the context of this problem in 20 patients without cardiac disease undergoing cancer chemotherapy including anthracyclines. Doppler echocardiography was performed before the first session of chemotherapy and at the end of treatment, 6 +/- 4 months later. After a total cumulative dose of 227 +/- 91 mg/m2 of doxorubicine, there were no changes in left ventricular ejection fraction but a significant decrease in mitral E wave velocity (p = 0.04) and in E/A ratio (p = 0.01), suggesting early changes in left ventricular relaxation. The Doppler tissue examination confirmed the presence of radial and longitudinal abnormalities in myocardial relaxation (decreases in myocardial E wave velocities of the posterior and lateral walls of the left ventricle, p = 0.02 and p = 0.01, respectively). The peak velocity of the myocardial systolic wave (Sm) was significantly decreased in the lateral wall (p = 0.02) and approached statistical significance in the posterior wall (p = 0.07). These results suggest concomitant changes in myocardial systolic and diastolic function with moderate doses of anthracyclines. Therefore, pulsed Doppler tissue examination enables earlier detection of left ventricular cardiotoxicity with anthracyclines than classical echocardiographic parameters.

Adult↗
PubMed2001

Regulation of agonist binding to rat ET(B) receptors by cations and GTPgammaS.

Endothelins exert their physiological effects through interaction with cell surface receptors that are members of the G-protein-coupled receptor family. The endothelin receptor subtype B (ET(B) receptor) is abundantly expressed in rat cerebellum. Since agonist binding to G-protein-coupled receptors may be modulated by cations and guanine nucleotides, we investigated the effects of cations and guanosine 5'-O-(2-thiotriphosphate) (GTPgammaS) on 125I-endothelin-1 (125I-ET-1) binding to rat cerebellar membranes. Both Na+ and Mg2+-stimulated 125I-ET-1 binding causing an increase in receptor affinity for the agonist. While the effect of the divalent cation was evident at relatively low concentrations (5-10 mM), the stimulatory activity of the monovalent cation appeared at relatively high concentrations (50 mM). Additive activities of 25-50 mM NaCl and 1 mM MgCl2 suggested that monovalent and divalent cations increased receptor affinity for ET-1 by different mechanisms. In the presence of 5 mM MgCl2, 50 mM NaCl caused an additional modest reduction of the Kd value. Whereas 5 mM MgCl2 affected the displacement curves of both ET-3 and suc-[Glu9, Ala11,15]-endothelin-1 (8-21) (IRL 1620), the influence of 50 mM NaCl on these curves was less substantial. All together, these results suggest that modulation of receptor affinity by NaCl depends on the nature of the displacing agonist. In the presence of 5 mM MgCl2 or 50 mM NaCl, a partial regulation of 125I-ET-1 binding by GTPgammaS was detectable, while in the absence of cations no GTPgammaS-dependent inhibition was evident.

Animals↗
PubMed2001

Novel N-(arylalkyl)indol-3-ylglyoxylylamides targeted as ligands of the benzodiazepine receptor: synthesis, biological evaluation, and molecular modeling analysis of the structure-activity relationships.

A series of N-(arylalkyl)indol-3-ylglyoxylylamides (4-8) was synthesized as ligands of the benzodiazepine receptor (BzR) and tested for their ability to displace [(3)H]flumazenil from bovine brain membranes. The new compounds, bearing a branched (4) or a geometrically constrained benzyl/phenylethyl amide side chain (5-8), represent the continuation of our research on N-benzylindol-3-ylglyoxylylamides 1 (Da Settimo et al., 1996), N'-phenylindol-3-ylglyoxylohydrazides 2 (Da Settimo et al., 1998), and N-(indol-3-ylglyoxylyl)alanine derivatives 3 (Primofiore et al., 1989). A few indoles belonging to the previously investigated benzylamides 1 and phenylhydrazides 2 were synthesized and tested to enrich the SARs in these two series. The affinities and the GABA ratios of selected compounds for clonal mammalian alpha(1)beta(2)gamma(2), alpha(3)beta(2)gamma(2), and alpha(5)beta(3)gamma(2) BzR subtypes were also determined. It was hypothesized that the reduced flexibility of indoles 4-8 would both facilitate the mapping of the BzR binding cleft and increase the chances of conferring selectivity for the considered receptor subtypes. In the series of indoles 4, the introduction of a methyl group on the benzylic carbon with the R configuration improved affinity of the 5-substituted (5-Cl and 5-NO(2)) derivatives, whereas it was detrimental for their 5-unsubtituted (5-H) counterparts. All S enantiomers were less potent than the R ones. Replacement of the methyl with hydrophilic substituents on the benzylic carbon lowered affinity. The isoindolinylamide side chain was tolerated if the 5-position was unsubstituted (K(i) of 5a = 123 nM), otherwise affinity was abolished (5b, c). All the 2-indanylamides 6 and (S)-1-indanylamides 8 were devoid of any appreciable affinity. The 5-Cl and 5-NO(2) (R)-1-indanylamides 7b (K(i) 80 nM) and 7c (K(i) 28 nM) were the most potent among the indoles 5-8 geometrically constrained about the side chain. The 5-H (R)-1-indanylamide 7a displayed a lower affinity (K(i) 675 nM). The SARs developed from the new compounds, together with those collected from our previous studies, confirmed the hypothesis of different binding modes for 5-substituted and 5-unsubstituted indoles, suggesting that the shape of the lipophilic pocket L(1) (notation in accordance with Cook's BzR topological model) is asymmetric and highlighted the stereoelectronic and conformational properties of the amide side chain required for high potency. Several of the new indoles showed selectivity for the alpha(1)beta(2)gamma(2) subtype compared with the alpha(3)beta(2)gamma(2) and alpha(5)beta(3)gamma(2) subtypes (e.g.: 4t and 7c bind to these three BzR isoforms with K(i) values of 14 nM, 283 nM, 239 nM, and 9 nM, 1960 nM, 95 nM, respectively). The GABA ratios close to unity exhibited by all the tested compounds on each BzR subtype were predictive of an efficacy profile typical of antagonists.

Amides↗
PubMed2001

Nitroxide TEMPOL impairs mitochondrial function and induces apoptosis in HL60 cells.

The piperidine nitroxide TEMPOL induces apoptosis in a number of tumor cell lines through free radical-dependent mechanisms. As mitochondria play a major role in apoptosis as both source and target for free radicals, the present study focuses on mitochondrial effects of TEMPOL in a human promyelocytic leukemic cell line (HL-60). On 24-h exposure to TEMPOL, the following alterations were observed: 1) decrease in both the intracellular and mitochondrial glutathione pools; 2) impairment of oxidative phosphorylation; and 3) decrease in mitochondrial membrane potential. In addition, TEMPOL was found to specifically target complex I of the respiratory chain, with minor effects on complexes II and IV, suggesting that mitochondrial effects might play a role in TEMPOL-induced oxidative stress and apoptosis, and that TEMPOL might sensitize tumor cells to the pro-apoptotic effects of cytotoxic agents.

Antioxidants↗
PubMed2001

Synthesis and preliminary pharmacological evaluation of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives as dopamine receptor ligands.

A series of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives (5a--e and 6a--e) were synthesized as conformationally rigid analogues of 1-benzyltetrahydroisoquinoline and evaluated for their affinity at D(1) and D(2) dopamine receptors. All compounds showed lower D(1) and D(2) affinities than dopamine. The 5-hydroxy-1-methyl-2,3,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline 5a and the 5,6-dihydroxy analogue 6a showed D(2) agonist activity. This was proved by their effects on prolactin release from primary cultures of rat anterior pituitary cells. Molecular modeling studies showed that the geometric parameters (namely the distances from meta and para hydroxyl oxygens to the nitrogen and the height of nitrogen from the hydroxylated phenyl ring plane) of the dopaminergic pharmacophore embedded in our compounds have lower values in comparison with those observed in D(1) and D(2) selective ligands.

Animals↗