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Biomedical subjects

M J García

Publications and source records attributed to M J García.

At least 19 recordsLinked to original sources
PubMed2006

Persistent increase of plasma butyryl/isobutyrylcarnitine concentrations as marker of SCAD defect and ethylmalonic encephalopathy.

High concentrations of butyryl/isobutyrylcarnitine (C(4)-carnitine) in plasma with increase of ethylmalonic acid (EMA) in urine point to different genetic entities, and further investigations are required to differentiate the possible underlying defect. Here we report three unrelated cases, two neurologically affected and one asymptomatic, with this abnormal metabolite pattern due either to mutations in the ETHE1 gene or to a short-chain acyl-CoA dehydrogenase (SCAD) defect.

Brain Diseases↗
PubMed2006

Renin-angiotensin system-regulating aminopeptidase activities are modified in the pineal gland of rats with breast cancer induced by N-methyl-nitrosourea.

OBJECTIVE: Pineal function has been considered particularly as a neuroendocrine modulator in hormone responsive tumors, like the hormone-dependent mammary tumors. The complexity of the gland function, moreover, is denoted by the presence of a local renin-angiotensin-system (RAS) that regulates melatonin biosynthesis. Classically, angiotensin II (Ang II) has been considered as the effector peptide of the RAS, but Ang II is not the only active peptide. Several of its degradation products, including angiotensin III (Ang III) and angiotensin IV (Ang IV) also possess biological functions. These peptides are formed via the activity of several aminopeptidases. Our aim is to know their role in the regulation of pineal RAS and breast cancer. DESIGN: Aminopeptidase N (APN), aminopeptidase B (APB) and aminopeptidase A (aspartyl- and glutamyl-aminopeptidase, APA) activities are measured in the pineal gland of rats with breast cancer induced by N-methyl nitrosourea (NMU). METHODS: Aminopeptidase activities were measured fluorimetrically using their corresponding aminoacyl-beta-naphthylamides as substrates. RESULTS: Specific APN and APB activities in pineal gland of controls and NMU-treated rats were not modified. Aspartyl aminopeptidase activity significantly decreased in NMU-treated rats when compared with control group. On the contrary, glutamyl aminopeptidase activity did not show significant differences between groups. CONCLUSIONS: We propose that the local RAS in pineal gland is modified in rats with breast cancer induced by NMU through the inhibition of AspAP activity, which may lead to increased levels of Ang II. Ang II could be responsible of the overproduction of melatonin, supporting a mechanism to restrain the promotion and/or progression of breast cancer.

Alkylating Agents↗
PubMed2005

Biweekly regimen of cisplatin, gemcitabine and vinorelbine for advanced non-small-cell lung cancer.

PURPOSE: Improving chemotherapeutic efficacy in non-small cell lung cancer (NSCLC) will require the development of new strategies to better use currently available agents. To assess the efficacy and safety of a biweekly regimen of cisplatin, gemcitabine and vinorelbine for advanced non-small-cell lung cancer. METHODS: Patients with selected stage IIIb (pleural effusion)/stage IV NSCLC, performance status of 0-2 and normal organ function were eligible. Treatment consisted of cisplatin 100 mg/m(2) on day 1 plus gemcitabine, 1,000 mg/m(2) and vinorelbine 25 mg/m(2) on days 1 and 15 every 28 days. RESULTS: Of the 40 patients enrolled and assessable for response, there were five (12.5%) with confirmed complete response and 14 (35%) with a confirmed partial response for an overall response rate of 47.5%. Nine patients had stable disease while 12 (30%) progressed. Median progression-free survival and overall survival for all patients were 6.3 and 11.1 months, respectively. Toxicity was principally hematologic, with grade 3-4 neutropenia in 30%, and grade 3-4 nausea/vomiting in 22.5%. There were no treatment-related deaths. CONCLUSIONS: The biweekly regimen of cisplatin, gemcitabine and vinorelbine is associated with a high rate of response, lesser toxicity than other three-drug regimens and no benefit of survival. Therefore, the regimen under study may be an appealing alternative when considering other treatment modalities for advanced lung cancer, such as neoadjuvant therapy.

Adult↗
PubMed2005

Pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes of rats with mammary gland cancer induced by N-methyl nitrosourea.

Pyrrolidon carboxypeptidase is an omega-peptidase that hydrolyses N-terminal pyroglutamyl residues from biologically active peptides such as gonadotropin-releasing and thyrotrophin-releasing hormones. We previously described a decrease in both rat and human pyrrolidon carboxypeptidase activity with breast cancer, suggesting that gonadotropin-releasing hormone may be an important local intracrine, autocrine and/or paracrine hormonal factor in the pathogenesis of breast cancer while playing a role in the tumoral process. However, the other susceptible substrate of pyrrolidon carboxypeptidase, thyrotrophin-releasing hormone, may also be modified with breast cancer, supporting an association between breast cancer and thyroid disorders. The present work analyses soluble and membrane-bound pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes in N-methyl nitrosourea-induced breast cancer in rats. Our aim was to determine the possible relationship between gonadotropin-releasing hormone and thyrotrophin-releasing hormone regulation through pyrrolidon carboxypeptidase activity. We propose that pyrrolidon carboxypeptidase activity dysregulation at various local and systemic levels may participate in the initiation, promotion and progression of breast cancer induced in rat by N-methyl nitrosourea through the increase in gonadotropin-releasing hormone. Since pyrrolidon carboxypeptidase activity also acts on thyrotrophin-releasing hormone, the dysregulation of this enzyme's activity could indirectly affect hypothalamus-pituitary-thyroid axis function, and thus potentially represent a link between the diseases of thyroid and breast cancer.

Animals↗
PubMed2004

Chronic ethanol intake modifies renin-angiotensin system-regulating aminopeptidase activities in mouse cerebellum.

In developing cerebellum, where critical periods of vulnerability have been established for several basic substances, it has been extensively studied the wide array of abnormalities induced by exposure to ethanol (EtOH). However, little is known about the effects of EtOH consumption on cerebellar functions in adult individuals. Several studies show participation in cognitive activities to be concentrated in the lateral cerebellum (hemispheres), whereas basic motor functions such as balance and coordination are represented in the medial parts of the cerebellum (vermis and paravermis). In addition to the circulating renin angiotensin system (RAS), a local system has been postulated in brain. The effector peptides of the RAS are formed via the activity of several aminopeptidases (AP). The present work analyses the effect of chronic EtOH intake on the RAS-regulating AP activities in the soluble and membrane-bound fractions of two cerebellar locations: the hemispheres and the vermis. We hypothesize that cerebellar RAS is involved in basic motor functions rather than in cognitive activities.

Aminopeptidases↗
PubMed2004

Serum oxytocinase activity is related to tumor growth parameters in N-methyl nitrosourea induced rat breast cancer.

Oxytocinase has been reported to hydrolyse the peptide hormone oxytocin (OT). We have previously described changes in oxytocinase activity in human breast cancer, where a highly significant increase occurred in tumoral tissue. In the present work, we analysed oxytocinase activity in serum of rats with breast cancer induced by N-methyl-nitrosourea (NMU). We also correlated these data with the number and size of tumors and the body weight of the animals to evaluate the putative value of this activity as a biological marker of the disease. Our results confirm the involvement of OT in carcinogenesis and suggest a mayor role for oxytocinase activity in the development of breast cancer.

Animals↗
PubMed2003

Optimization of making barrel-fermented dry muscatel wines.

The optimization of making barrel-fermented muscatel wines requires determining what type of must clarification is most suitable for the quality of the wine, as well as what type of barrel will yield the most acceptable wines. This is achieved by adding pectolytic enzymes to clarify part of the muscatel must statically; the rest is clarified by vacuum filtration. The musts obtained are fermented in French and American oak barrels and, once fermentation has ceased, they are kept with their lees for 2 months, with periodic stirring. Eleven conventional parameters and 31 volatile compounds were quantified, and a sensory analysis of the wines was produced, which led us to conclude that static clarification with pectolytic enzymes from the muscatel musts produces the best-structured wines and the larger content of higher alcohols, esters, and terpenic compounds. The wines fermented in American oak barrels received the highest overall marks, which may be due to the greater aromatic complexity given off by the compounds in the wood.

Alcohols↗
PubMed2003

Serum pyrrolidone carboxypeptidase activity in N-methyl-nitrosourea induced rat breast cancer.

Pyrrolidone carboxypeptidase (Pcp) (E.C. 3.4.19.3) is an omega peptidase widely distributed in animal fluids and tissues and hydrolyses N-terminal pyroglutamic residues from biologically active peptides such as gonadotropin releasing hormone (GnRH). Previous results obtained by us showed a decrease in human breast cancer Pcp activity, suggesting that this enzyme activity or its putative substrates may play a major role in breast cancer pathogenesis. The aim of the present work is to analyse serum Pcp activity in N-methyl-nitrosourea (NMU) induced rat mammary tumours using pyroglutamyl-beta-naphthylamide as substrate. Serum Pcp activity was significantly lower in NMU-treated rats than in controls. Moreover, multiple regression analysis showed a significant correlation between Pcp activity and the number and size of tumours and the body weight of the animals. Since NMU-induced carcinomas are mainly oestrogen-dependent, the decrease observed in Pcp activity may reflect an increase in circulating levels of GnRH that lead to an increase in gonadal steroid hormones production responsible, at least in part, for the initiation and promotion of the disease.

Animals↗
PubMed2002

Effects of exogenous fatty acids and cholesterol on aminopeptidase activities in rat astroglia.

Several studies have addressed the interaction between fatty acids and lipids with central nervous system peptides. Because aminopeptidases (AP) are involved in the regulation of neuropeptides, this work studies several AP expressed in cultured astroglia, after exogenous addition of oleic and linoleic fatty acids and cholesterol to the culture medium. Alanyl-AP, arginyl-AP, cystyl-AP, leucyl-AP, tyrosyl-AP and pyroglutamyl-AP activities were analysed in whole cells using the corresponding aminoacyl-beta-naphthylamides as substrates. Oleic acid inhibits alanyl-AP, cystyl-AP and leucyl-AP activities, whereas linoleic acid inhibits alanyl-AP, arginyl-AP and tyrosyl-AP activities. Neither oleic acid nor linoleic acid modifies pyroglutamyl-AP activity. In contrast, cholesterol increases arginyl-AP, cystyl-AP, leucyl-AP, tyrosyl-AP and pyroglutamyl-AP activities, although it does not modify alanyl-AP activity. The changes reported here suggest that oleic and linoleic fatty acids and cholesterol can modulate peptide activities via their degradation route involving aminopeptidases; each of them being differentially regulated.

Aminopeptidases↗
PubMed2002

Effects of dietary cholesterol on pyroglutamyl aminopeptidase activity in mouse frontal cortex, pituitary, and adrenal glands.

Pyroglutamyl aminopeptidase (pGluAP) is an omega peptidase that hydrolyzes biologically active peptides, such as thyrotropin-releasing hormone (TRH), with neuronal and extraendocrine functions. We analyzed the effects of a cholesterol-enriched diet on soluble and membrane-bound pGluAP activity in frontal cortex, pituitary and adrenal glands of male and female mice using fluorimetric assays. Significant increases were observed in soluble pGluAP activity in the frontal cortex and adrenal glands in males and in the pituitary in females. Membrane-bound pGluAP activity was increased in the frontal cortex and pituitary of males and females after the mice were fed a cholesterol-enriched diet. These increases may produce changes in the metabolism of endogenous substrates, including TRH, which may be related to alterations in its neuromodulator functions and to the possible relationship between TRH and other neurotransmitter systems.

Adrenal Glands↗
PubMed2002

Screening for adenylosuccinate lyase deficiency: clinical, biochemical and molecular findings in four patients.

Adenylosuccinate lyase deficiency is an autosomal recessive defect of purine metabolism. Succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr) are the disease marker metabolites in physiological fluids. The Bratton-Marshall test for detection of SAICAr in urine has been added to the selective screening for inborn errors of metabolism that is carried out in our lab. During the last three years, around 2,000 patients have been screened by this method, resulting in the detection of four new cases with this disease. They all presented with severe psychomotor delay, hypotonia and refractory epilepsy since the neonatal period. The S-Ado/SAICAr ratio in cerebrospinal fluid was below 2, indicating that they correspond to the most severe form of the disease. New missense mutations were found in a heterozygous fashion in three patients. The study of purines in all patients with neurological disease of unknown etiology is highly recommended.

Adenylosuccinate Lyase↗
PubMed2002

Preclinical pharmacokinetics of statins.

This review summarizes the pharmacokinetic properties of HMG-CoA reductase inhibitors (or statins) reported in animals. Lovastatin and simvastatin are administered as lactone prodrugs in contrast to other statins, which are generally formulated in the pharmacological active hydroxy acid form. Pharmacokinetics vary with the statin and animal species considered. Oral absorption is rapid and the bioavailability low due to an extensive first-pass metabolism. Pitavastatin is the exception, with high bioavailability in all species except monkeys (80% vs. 18%). Plasma protein binding is high for all statins (> 95%) except pravastatin (60%). Regardless of the dosing schedule (single or multiple), animal species and statin, the highest tissue levels are found in the liver--the target organ. Elimination is rapid with metabolism being the main elimination route for all statins, except for pitavastatin, which is only slightly metabolized, and pravastatin, which aside from metabolism is also eliminated by renal excretion. Statins undergo enterohepatic circulation and are recovered mainly in feces via bile, the extent of which is species-dependent. Metabolism varies with the statin and animal species, particularly the beta-oxidation of the dihydroxy heptanoic side chain that occurs primarily in rodents.

Absorption↗
PubMed2001

Pituitary aminopeptidase activities involved in blood-pressure regulation are modified by dietary cholesterol: sex differences.

Given that the existence of a local renin-angiotensin system (RAS) in the pituitary and its participation in the regulation of blood pressure and other biological functions are widely accepted, the aim of this work is to analyze the influence of dietary cholesterol on the activity of the enzymes involved in the metabolism of the effector peptides of the renin-angiotensin system (angiotensin II and III) and vasopressin, in the pituitary of male and female mice fed on a cholesterol-enriched diet (1% cholesterol and 0.5% cholic acid). Soluble and membrane-bound pituitary aminopeptidase A (aspartyl- and glutamyl-aminopeptidase), aminopeptidase M (alanyl-aminopeptidase), aminopeptidase B (arginyl-aminopeptidase) and cystinyl-aminopeptidase activities were fluorimetrically measured. In female mice, cholesterol-enriched diet produced a significant increase in soluble aspartyl- and membrane-bound aspartyl- and glutamyl-aminopeptidase activities, and a significant decrease in membrane-bound alanyl-, arginyl- and cystinyl-aminopeptidase activities. In male mice, after feeding the diet, a significant increase in soluble glutamyl- and membrane-bound arginyl-aminopeptidase activities was observed. Our results indicate differential effects of dietary cholesterol on the metabolism of angiotensin II and III and vasopressin in the pituitary of male and female mice.

Animals↗
PubMed2001

Geochemical evolution of amino acids in dentine of Pleistocene bears.

A linear correlation was established between aspartic acid racemization ratio from cave bear dentine collagen and absolute dating. The high correlation coefficient obtained allowed age calculation through amino acid racemization. Aspartic acid and glutamic acid racemization kinetics have also been explored in dentine from a North American black bear (Ursus americanus Pallas). Three sample sets were prepared for kinetic heating experiments in nitrogen atmosphere: one water soaked, one with a water-saturated nitrogen atmosphere, and one without any moisture. It was possible to show that the presence of water is a factor controlling amino acid racemization rate. The aspartic acid in a heating experiment at 105 degrees C shows an "apparent kinetics reversal" which can be explained by a progressive hydrolysis of amino acid chains (proteins and polypeptides). Because of the low potential of collagen preservation over long periods of time, the apparent kinetics reversal phenomenon will not affect the dating of old material where no traces of collagen remain. An apparent kinetics reversal was not observed in glutamic acid, which racemizates more slowly.

Age Determination by Teeth↗
PubMed2001

[Tomographic studies of myocardial perfusion normality with 99m Tc-Tetrofosmin. Spanish multicenter study].

As a first phase in a nationwide multicenter study to obtain myocardial perfusion normality patterns, this work presents the study design and quality control methodology used to guarantee that the gammacameras fulfilled some minimum quality requirements. The following aspects were considered in the study design in order to guarantee the homogeneity and interchangeability of the results: creation and structure of the work group, data interchange system, data selection and acquisition, centralized archiving and processing, assessment system, study acceptance criteria and distribution of the results. To carry out the instrumental quality control, three phantom studies were established, one to control the rotation center, another to verify tomographic uniformity and a third to simulate the shape and orientation of the left ventricle. The three phantoms circulated through all of the 18 participating centers in this project, which corresponded to 19 gammacameras. Very strict guidelines had to be followed in the acquisition and processing of these phantom studies. If any camera and/or center did not fulfill the criteria established, it was advised of the problem detected in order to correct it. Once the defect was repaired, all the phantoms were sent again for verification. Uniformity of the rotation center was quantified by means of the eccentricity of a 360 degrees orbit, admitting up to a maximum of 10%. Tomographic uniformity was visually assessed, taking in account the number of slices with rings and their contrast and finally no artifacts could be present in the reconstructed study of the ventricle. The center of rotation was within limits in all the cameras except one case while the tomographic uniformity was incorrect in 6 cases. All the departments, except one, corrected the defects detected, and passed the acceptance test. The results made it possible to guarantee adequate homogeneity and instrumental quality in this multicenter study.

Coronary Circulation↗