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Biomedical subjects

L Toma

Publications and source records attributed to L Toma.

At least 19 recordsLinked to original sources
PubMed2000

Anti-tumor-promoting effects of glycoglycerolipid analogues on two-stage mouse skin carcinogenesis.

Four glycoglycerolipid analogues, 1-O-hexanoyl-2-O-beta-D-glucopyranosyl-sn-glycerol (1), 1-O-hexanoyl-2-O-beta-D-galactopyranosyl-sn-glycerol (2), 2-O-(6-O-hexanoyl-beta-D-galactopyranosyl)-sn-glycerol (3) and 2-O-(6-O-hexanoyl-alpha-D-galactopyranosyl)-sn-glycerol (4), potent in vitro inhibitors of 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation, were submitted to an in vivo two-stage mouse skin carcinogenesis test, using dimethylbenz[a]anthracene (DMBA) and TPA. The study was extended to two deacylated galactosylglycerol structures, 1-O-beta-D-galactopyranosyl-sn-glycerol (5) and 3-O-beta-D-galactopyranosyl-sn-glycerol (6). All the tested compounds exhibited remarkable anti-tumor-promoting effects on mouse skin tumor promotion, the 1-hexanoate 2 being the most active among the glycoglycerolipids until now studied.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2000

Ab initio and density functional evaluations of the molecular conformations of beta-caryophyllene and 6-hydroxycaryophyllene.

The four conformations of beta-caryophyllene (alphaalpha, alphabeta, betaalpha, and betabeta) were investigated ab initio at the 6-31G/HF and MP2 levels and additionally with density functional methods (B3LYP/6-31G), as it concerns their relative thermodynamic stabilities. The alphaalpha is predicted to be the most stable geometry, in agreement with low-temperature NMR measurements. In the case of 6-hydroxycaryophyllene, the alphaalpha is still the most stable conformation when the configuration at C-6 is S, but when the configuration is reversed to R the betabeta geometry becomes the most stable one. This is again in agreement with NMR data. On the other hand, for both molecules the AM1 semiempirical model Hamiltonian fails to predict the alphaalpha as a low-energy geometry, mainly due to an incorrect description of the cyclobutane ring puckering. The interconversion paths among the different minima are also analyzed and discussed. The solvent effect (either chloroform or water) on the stability of the different conformers of beta-caryophyllene and 6-hydroxycaryophyllene was studied in the polarizable continuum model framework.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Conformational analysis and stability of collagen peptides by CD and by 1H- and 13C-NMR spectroscopies.

Four small type I collagen CNBr peptides containing complete natural sequences were purified from bovine skin and investigated by CD and 1H- and 13C-nmr spectroscopies to obtain information concerning their conformation and thermal stability. CD showed that a triple helix was formed at 10 degrees C in acidic aqueous solution by peptide alpha l(I) CB2 only, and to lesser extent, by alpha 1(I) CB4, whereas peptides alpha 1(I) CB5 and alpha 2(I) CB2 remained unstructured. Analytical gel filtration confirmed that peptides alpha 1(I) CB2 and alpha 1(I) CB4 only were able to form trimeric species at temperature between 14 and 20 degrees C, and indicated that the monomer = trimer equilibrium was influenced by the chaotropic nature of the salt present in the eluent, by its concentration, and by temperature variations. CD measurements at increasing temperatures showed that alpha 1(I) CB2 was less stable than its synthetic counterpart due to incomplete prolyl hydroxylation of the preparation from the natural source. 1H- and 13C-nmr spectra acquired in the temperature range 0-47 and 0-27 degrees C, respectively, indicated that with decreasing temperature the most abundant from of alpha 1(I) CB2 was in slow exchange with an assembled form, characterized by broad lines, as expected for the triple-helical conformation. A large number of trimer cross peaks was observed both in the proton and carbon spectra, and these were most likely due to the nonequivalence of the environments of the three chains in the triple helix. This nonequivalence may have implications for the aggregation of collagen molecules and for collagen binding to other molecules. The thermal transition from trimer to monomer was also monitored by 1H-nmr following the change in area of the signal belonging to one of the two beta protons of the C-terminal homoserine. The unfolding process was found to be fully reversible with a melting temperature of 13.4 degrees C, in agreement with CD results. The qualitative superposition of the melting curves obtained by CD for the peptide bond characteristics and by nmr for a side chain suggests that triple-helical backbone and side chains constitute a single unit.

Amino Acid Sequence↗
PubMed2000

Olanzapine in severe Gilles de la Tourette syndrome: a 52-week double-blind cross-over study vs. low-dose pimozide.

We selected four patients with severe Gilles de la Tourette syndrome, high frequency of tics (two to ten per minute), vocalizations, and lack of comorbidity. These patients (aged 19-40 years) underwent a 52-week double-blind cross-over study with olanzapine (5 and 10 mg daily) vs. low-dose pimozide (2 and 4 mg daily). The reduction in rating scale scores for the syndrome was highly significant with 10 mg olanzapine vs. basal and vs. 2 mg pimozide, and was significant for 5 mg olanzapine vs. 4 mg pimozide. Only moderate sedation was reported by one patient during olanzapine treatment while three complained of minor motor side effects and sedation during pimozide treatment. At the end of the study all patients opted for olanzapine treatment.

Adult↗
PubMed2000

Synthesis, modelling, and mu-opioid receptor affinity of N-3(9)-arylpropenyl-N-9(3)-propionyl-3,9-diazabicycl.

A series of N-3-arylpropenyl-N-9-propionyl-3,9-diazabicyclo[3.3.1]nonanes (1a-g) and of reverted N-3-propionyl-N-9-arylpropenyl isomers (2a-g), as homologues of the previously reported analgesic 3,8-diazabicyclo[3.2.1]octanes (I-II), were synthesized and evaluated for the binding affinity towards opioid receptor subtypes mu, delta and kappa. Compounds 1a-g and 2a-g exhibited a strong selective mu-affinity with Ki values in the nanomolar range, which favourably compared with those of I and II. In addition, contrary to the trend observed for DBO-I, II, the mu-affinity of series 2 is markedly higher than that of the isomeric series 1. This aspect was discussed on the basis of the conformational studies performed on DBN which allowed hypotheses on the mode of interaction of these compounds with the mu receptor.

Analgesics↗
PubMed2000

The opioid-receptor-like 1 (ORL-1) as a potential target for new analgesics.

Anew sequence, which encoded a novel G protein-coupled receptor, was disclosed by two different groups, using the nucleic acid probes based on the delta opioid receptor, first cloned in 1992. The new receptor, which Meunier called opioid-receptor-like 1 (ORL-1), was shown to share high homology with the opioid receptors and therefore thought to be a potential target for new analgesics. In this respect, the present review reports on the literature referring to ORL-1, to its natural ligand (nociceptin or orphanin FQ) and to several synthetic analogues recently described, both as agonists or antagonists at the receptor.

Amino Acid Sequence↗
PubMed2000

Glycoglycerolipid analogues active as anti-tumor-promoters: the influence of the anomeric configuration.

The in vitro anti-tumor promoting effect of monohexanoates of 2-O-alpha-D-gluco- and galactopyranosyl-sn-glycerol on the 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation was evaluated and compared to the potencies of the corresponding beta-anomers. The results show that the inversion of the anomeric configuration from beta to alpha does not seem to significantly influence the activity, which is present, as for the beta-anomers, even at 1x10 mol ratio without any cytotoxicity.

Anticarcinogenic Agents↗
PubMed2000

Prevalence and risk factors for human herpesvirus 8 infection in northern Cameroon.

BACKGROUND: The modes of transmission of HHV-8 are still unclear. GOAL: To evaluate the distribution and transmission of HHV-8 infection. DESIGN: Serosurvey conducted in a Cameroon hospital among 292 persons, including children (5-10 years), adolescents (15-20 years), and adults (30-40 years). Antibodies against lytic and latent antigens to HHV-8 were detected by immunofluorescence assay; antibodies against Epstein-Barr virus viral antigens were detected by enzyme-linked immunoabsorbent assay. RESULTS: The prevalence of HHV-8 antilytic antibodies remained stable and was 39.8% among children, 51.5% among adolescents, and 61.8% among adults. Epstein-Barr virus seroprevalence was high among children, and remained stable among adolescents and adults. A history of sexually transmitted diseases was an independent determinant of HHV-8 infection (adjusted odds ratio 2.47; 95% CI 1.09-4.91). CONCLUSION: The high prevalence of HHV-8 infection among children indicates nonsexual modes of transmission in Cameroon, with sexual transmission occurring among adolescents and adults.

Adolescent↗
PubMed1999

Synthesis and enantiopharmacology of new AMPA-kainate receptor agonists.

Regioisomeric 3-carboxyisoxazolinyl prolines [CIP-A (+/-)-6 and CIP-B (+/-)-7] and 3-hydroxyisoxazolinyl prolines [(+/-)-8 and (+/-)-9] were synthesized and assayed for glutamate receptor activity. The tests were carried out in vitro by means of receptor binding techniques, second messenger assays, and the rat cortical wedge preparation. CIP-A showed a good affinity for both 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and kainic acid (KAIN) receptors. These results were confirmed in the cortical slice model where CIP-A displayed an EC(50) value very close to that of AMPA. The convulsant properties of all the compounds were evaluated in vivo on DBA/2 mice after icv injection. CIP-A showed a convulsant activity, measured as tonus and clonus seizures, 18-65 times higher than that produced by AMPA. It was also quite active after ip administration, since it induced seizures in mice at doses as low as 3.2 nmol/mouse. On the basis of the above-reported results we prepared and tested the enantiomers of CIP-A and CIP-B, obtained by reacting (S)-3,4-didehydroproline and (R)-3,4-didehydroproline, respectively, with ethoxycarbonylformonitrile oxide. In all the tests the S-form, CIP-AS [(-)-6], emerged as the eutomer evidencing common stereochemical requirements with the reference compounds AMPA and KAIN. Through modeling studies, carried out on CIP-A, AMPA, and KAIN, active conformations for CIP-AS and AMPA at AMPA receptors as well as for CIP-AS and KAIN at KAIN receptors are suggested.

Animals↗
PubMed1999

Inhibitory effects of monoacylated 2-O-beta-galactosylglycerols on Epstein-Barr virus activation: the significant role of the hexanoyl chain.

Three series of monoacyl-2-O-beta-D-galactosylglycerols bearing an acyl chain of varying length, from C4 to C10, were studied due to their antitumor promoting effects on the activation of the Epstein-Barr virus early antigen (EBV-EA), such activation being induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). This study indicates that it is more the length of the acyl chain that is important for the activity, six carbon atoms resulting in maximum effect, rather than the position of the ester function and the nature of the sugar (galactose or glucose).

Antigens, Viral↗
PubMed1999

Novel adrenoceptor antagonists with a tricyclic pyrrolodipyridazine skeleton.

A still unknown tricyclic heterocyclic system (5) was synthesized from 6-hydroxy-2-methylpyridazin-3-one and its structure identified as 2,8-dichloro-6-methylpyrrolo[1,2-b:3,4-d']dipyridazin-5(6H)- one by spectroscopic investigations. Selective condensation of 5 with 2-[4-(2-substituted-phenyl)piperazin-1-yl]ethylamine gave the 2-arylpiperazinylethylamino-8-chloro derivatives 6a-c, which were investigated in binding studies toward the three alpha1-adrenergic and 5-HT1A-serotonergic receptor subtypes. They displayed high potency on all the assays and some selectivity for alpha1a and alpha1d subtypes.

Adrenergic Antagonists↗
PubMed1999

Chemoenzymatic synthesis and antitumor promoting activity of 6'- and 3-esters of 2-O-beta-D-glucosylglycerol.

Through a simple chemoenzymatic approach 6'- and 3-esters of 2-O-beta-D-glucosylglycerol 1, with short-medium length fatty acid acyl chains, were prepared. The study of their in vitro antitumor promoting effect on Epstein-Barr virus early antigen (EBV-EA) activation, in comparison with that of the 1-esters previously described, confirms the significant activity of such monoacylated glycoglycerolipid analogues and establishes for the glucose series that the 1-substitution and the hexanoyl chain are the proper structural features for the maximum activity.

Anticarcinogenic Agents↗
PubMed1999

Headache in children with centrotemporal spikes.

The aim of the study was to evaluate the long-term evolution of headache associated with rolandic centrotemporal spikes (CTS). The patient group consisted of a group of 32 children who suffered from headache and presented CTS at electroencephalogram (EEG). As the control group, we selected 52 sex- and age-matched children with headache without any EEG abnormalities. During a follow-up of 5 years none of them showed epileptic seizures. The number of headache attacks decreased in the majority of patients, as in the controls. A good correlation could be identified between CTS and the number of headaches attacks both at baseline (r = 0.58, P < 0.001) and at follow-up (r = 0.64, P < 0.001). In four children (12.5%), the frequency of headache attacks increased and this increase was associated with a higher frequency of CTS. In two patients, a change in the EEG pattern was observed during follow-up, with a 'migration' of the epileptiform complex from central to parietooccipital leads. In conclusion, these findings confirm that CTS are not pathognomonic of centrotemporal epilepsy and that evolution of CTS and headache in children are statistically related.

Adolescent↗
PubMed1999

Folding simulation of protein models on the structure-based cubo-octahedral lattice with the Contact Interactions algorithm.

Computer simulations of protein models on lattices have been widely used as an aid in the study of protein folding process. Following the suggestion of Raghunathan and Jernigan (1997, Protein Sci. 6:2072-2083) that the cubooctahedral lattice can allow a more realistic representation of proteins than other lattices, we propose here the use of a new set of internal coordinates theta for the description of a protein model on this lattice. An easy procedure for the conversion of the theta coordinates to the Cartesian coordinates is also described. When the Contact Interaction approach, already proposed by us for simulations on square or cubic lattices, was applied to the cubo-octahedral lattice, the system obeyed the correct thermodynamics derived from the definition of energy. Thus, lattice simulations of protein models, in which secondary structure elements such as alpha-helices or beta-strands can be easily identifiable, can be performed.

Algorithms↗
PubMed1999

Heparan sulfates and heparins: similar compounds performing the same functions in vertebrates and invertebrates?

The distribution and structure of heparan sulfate and heparin are briefly reviewed. Heparan sulfate is a ubiquitous compound of animal cells whose structure has been maintained throughout evolution, showing an enormous variability regarding the relative amounts of its disaccharide units. Heparin, on the other hand, is present only in a few tissues and species of the animal kingdom and in the form of granules inside organelles in the cytoplasm of special cells. Thus, the distribution as well as the main structural features of the molecule, including its main disaccharide unit, have been maintained through evolution. These and other studies led to the proposal that heparan sulfate may be involved in the cell-cell recognition phenomena and control of cell growth, whereas heparin may be involved in defense mechanisms against bacteria and other foreign materials. All indications obtained thus far suggest that these molecules perform the same functions in vertebrates and invertebrates.

Animals↗
PubMed1998

The putative heparin-specific N-acetylglucosaminyl N-Deacetylase/N-sulfotransferase also occurs in non-heparin-producing cells.

N-Deacetylation and N-sulfation of N-acetylglucosamine of heparin and heparan sulfate are hypothesized to be mediated by different tissue-specific N-acetylglucosaminyl N-deacetylases/N-sulfotransferases, which in turn lead to the higher L-iduronic acid and sulfate content of heparin versus heparan sulfate. Furthermore, the putative heparin-specific N-acetylglucosaminyl N-deacetylase/N-sulfotransferase has been reported to require auxiliary proteins for its N-acetylglucosaminyl N-deacetylase activity in vivo based on its requirement of polycations in vitro. We have now found that cells derived from embryonic bovine trachea, a tissue that does not synthesize heparin, has a N-acetylglucosaminyl N-deacetylase/N-sulfotransferase, which has 95% amino acid sequence identity to the above enzyme postulated to be involved in the biosynthesis of heparin. Both enzymes also have very similar affinity for their substrates. The trachea enzyme does not require additional effectors for its N-acetylglucosaminyl N-deacetylase activity in vitro even though its biochemical characteristics are virtually the same as the enzyme previously isolated from cells of a heparin-producing mastocytoma tumor. The trachea enzyme, which is encoded by an abundant 4.6-kilobase mRNA, like mastocytoma cells, has 70% amino acid sequence identity with the corresponding enzyme from rat liver postulated to participate in the biosynthesis of heparan sulfate. Heparan sulfate synthesized by trachea cells has a higher content of sulfated iduronic acid than from other tissues. Together, the above results strongly suggest that the above enzymes from mastocytoma, liver, and trachea, per se, are not solely responsible for the selective tissue-specific synthesis of heparin or heparan sulfate; more likely cellular factors, additional enzymes, and availability of substrates in the Golgi lumen also play important roles in the differential synthesis of the above proteoglycans.

Acetyltransferases↗
PubMed1998

Mono- and disubstituted-3,8-diazabicyclo[3.2.1]octane derivatives as analgesics structurally related to epibatidine: synthesis, activity, and modeling.

A series of 3,8-diazabicyclo[3.2.1]octanes substituted either at the 3 position (compounds 1) or at the 8 position (compounds 2) by a chlorinated heteroaryl ring were synthesized, as potential analogues of the potent natural analgesic epibatidine. When tested in the hot plate assay, the majority of the compounds showed significant effects, the most interesting being the 3-(6-chloro-3-pyridazinyl)-3,8-diazabicyclo[3.2.1]octane (1a). At a subcutaneous dose of 1 mg/kg, 1a induced a significant increase in the pain threshold, its action lasting for about 45 min. 1a also demonstrated good protection at a dose of 5 mg/kg in the mouse abdominal constriction test, while at 20 mg/kg it completely prevented the constrictions in the animals. Administration of naloxone (1 mg/kg i.p.) did not antagonize its antinociception while mecamylamine (2 mg/kg i.p.) did, thus suggesting the involvement of the nicotinic system in its action. Binding studies confirmed high affinity for the alpha 4 beta 2 nAChR subtype (Ki = 4.1 +/- 0.21 nM). nAChR functional activity studies on three different cell lines showed that 1a was devoid of any activity at the neuromuscular junction. Finally, due to the analogy in their pharmacological profile with that of epibatidine, compounds were compared from a structural and conformational point of view through theoretical calculations and high-field 1H NMR spectroscopy. Results indicate that all of them present one conformation similar to that of epibatidine.

Abdominal Muscles↗