Biomedical subjects

Arne K Sandvik

Publications and source records attributed to Arne K Sandvik.

9 recordsLinked to original sources

PubMed2003

Liver gene expression in rats in response to the peroxisome proliferator-activated receptor-alpha agonist ciprofibrate.

Fibrate class hypolipidemic drugs such as ciprofibrate activate the peroxisome proliferator-activated receptor-alpha (PPARalpha), which is involved in processes including lipid metabolism and hepatocyte proliferation in rodents. We examined the effects of ciprofibrate (50 mg/kg body wt per day for 60 days) on liver gene expression in rats using cDNA microarrays. The 60-day dosing period was chosen to elucidate both the metabolic and proliferative actions of this substance, while avoiding confounding effects from the hepatic carcinogenesis seen during more long-term stimulation. Ciprofibrate changed the expression of many genes including previously known PPARalpha agonist-responsive genes involved in processes such as lipid metabolism and inflammatory responses. In addition, many novel candidate genes involved in sugar metabolism, transcription, signal transduction, cell proliferation, and stress responses appeared to be differentially regulated in ciprofibrate-dosed rats. Ciprofibrate also resulted in significant increases in liver weight and hepatocyte proliferation. The cDNA microarray results were confirmed by Northern blot analysis for selected genes. This study thus identifies many genes that appear to be differentially regulated in ciprofibrate-dosed rats, and some of these are potential targets of PPARalpha. The functional diversity of these candidate genes suggests that most of them are likely to be differentially regulated as indirect consequence of the many processes affected by ciprofibrate in rodent liver. Although caution is advisable in the interpretation of genome-wide expression data, the genes identified in the present study provide candidates for further studies that may give new insight into the mechanisms of action of peroxisome proliferators.

Animals↗

PubMed2003

Spontaneous ECL cell carcinomas in cotton rats: natural course and prevention by a gastrin receptor antagonist.

In our inbred strain of cotton rats (Sigmodon hispidus) 50% of the females develop spontaneous ECL cell-derived tumors in the acid-producing part of the stomach due to hypergastrinemia secondary to gastric hypoacidity. Although the mechanism behind the hypoacidity is unknown, the female cotton rat is an excellent model for studying ECL cell-related tumorigenesis. In this study we wanted to explore the malignancy potential of these tumors and the ability of a gastrin receptor antagonist (YF476) to prevent their development. First, nine hypergastrinemic female cotton rats (10 months of age) were diagnosed by laparotomy as having gastric tumors. They were killed 6 months later. Second, 18 female cotton rats (2 months of age) were dosed monthly for 6 months with YF476 (500 micro mol/kg body wt) by s.c. injection, while 21 age-matched animals received vehicle. Samples from each stomach were collected for histology, immunohistochemistry and northern blot analysis. The gastric tumors harbored cells with immunohistochemical features of ECL cells. The tumors were found at times to invade and penetrate the stomach wall and to metastasize to perigastric sites. ECL-derived tumor cells were discovered in peritoneal fluid. At death only 1 out of 18 animals given YF476 displayed carcinomas (invasive growth), compared with 7 out of 21 in the vehicle dosed control group (P = 0.048). The spontaneous gastric tumors in cotton rats derived from ECL cells. The tumors were able to penetrate the stomach wall and to metastasize by intracavital seeding. Gastrin receptor blockade lowered the incidence of such tumors. We propose that the tumors are ECL cell carcinomas and that gastrin is the driving force behind the transformation from normal to malignant ECL cells.

Animals↗

PubMed2003

Predicting gene ontology biological process from temporal gene expression patterns.

The aim of the present study was to generate hypotheses on the involvement of uncharacterized genes in biological processes. To this end, supervised learning was used to analyze microarray-derived time-series gene expression data. Our method was objectively evaluated on known genes using cross-validation and provided high-precision Gene Ontology biological process classifications for 211 of the 213 uncharacterized genes in the data set used. In addition, new roles in biological process were hypothesized for known genes. Our method uses biological knowledge expressed by Gene Ontology and generates a rule model associating this knowledge with minimal characteristic features of temporal gene expression profiles. This model allows learning and classification of multiple biological process roles for each gene and can predict participation of genes in a biological process even though the genes of this class exhibit a wide variety of gene expression profiles including inverse coregulation. A considerable number of the hypothesized new roles for known genes were confirmed by literature search. In addition, many biological process roles hypothesized for uncharacterized genes were found to agree with assumptions based on homology information. To our knowledge, a gene classifier of similar scope and functionality has not been reported earlier.

Animals↗

PubMed2002

PPAR alpha stimulates the rat gastrin-producing cell.

The peroxisome proliferator (PP) ciprofibrate stimulates gastrin-producing cells (G-cells) in the rat stomach by an unknown mechanism, inducing hypergastrinemia and secondary enterochromaffin-like (ECL) cell hyperplasia. Ciprofibrate is a specific ligand for the nuclear peroxisome proliferator-activated receptor alpha (PPAR alpha). To see whether the effects of ciprofibrate could be imitated, rats were given another PPAR alpha ligand WY-14643 or the PPAR gamma ligand troglitazone by gastric intubations daily for 28 and 56 days. Troglitazone failed to raise gastrin levels. WY-14643 increased gastrin mRNA abundance, G-cell density and induced hypergastrinemia, but to a lesser extent than ciprofibrate. ECL cell parameters increased in proportion with the relative hypergastrinemia. Ciprofibrate and WY-14643 altered the levels of acyl CoA-oxidase mRNA and PPAR alpha mRNA in antrum, but had no effect in corpus. The PPAR alpha receptor was found in at least some G-cells by immunostaining. This study supports the hypothesis that PPAR alpha specific ligands could stimulate the G-cells by acting locally from the stomach lumen through antral PPAR alpha.

Animals↗

PubMed2002

Rat parietal cells express CCK(2) receptor mRNA: gene expression analysis of single cells isolated by laser-assisted microdissection.

Gastrin plays a crucial role in maintaining a normal cellular composition and function of the oxyntic mucosa. It has been debated for decades whether parietal cells possess cholecystokinin-2 (CCK(2)) receptors and interact directly with gastrin. We investigated whether parietal cells express CCK(2) receptor mRNA by using new molecular biology techniques. Rat oxyntic mucosal cells were dispersed and enriched by elutriation, and single parietal and ECL cells were isolated from cell smears by means of laser microbeam microdissection and laser pressure catapulting. The mRNA from each single cell was isolated and subjected to one-step multiplex or conventional reverse transcription-polymerase chain reaction and subsequent nested PCR. Specific primers for the CCK(2) receptor were used in combination with primers for H,K-ATPase and histidine decarboxylase, specific markers for parietal and ECL cells, respectively. CCK(2) receptor mRNA was detected in 25% of the rat parietal cells and 40% of the ECL cells examined.

Animals↗

PubMed2002

Chronic exposure to carbon monoxide and nicotine: endothelin ET(A) receptor antagonism attenuates carbon monoxide-induced myocardial hypertrophy in rat.

The aims of the present study were to determine the effects of endothelin ET(A) receptor antagonism on carbon monoxide (CO)-induced cardiac hypertrophy and endothelin-1 (ET-1) expression and to compare myocardial effects of chronic nicotine with CO exposure. Female Sprague-Dawley rats (n = 84) were randomized to three groups exposed 20 h/day to CO (200 ppm), nicotine (500 microg/m3), or air for 14 consecutive days. In each exposure group, animals were randomized to ET(A) receptor antagonist LU 135252 in drinking water (0.5 mg/ml) or placebo. Myocardial ET-1 and atrial natriuretic peptide (ANP) expression was measured by competitive RT-PCR and plasma ET-1 by immunoassay. Carboxyhemoglobin was 22.1 +/- 0.3% in CO-exposed animals and 2.8 +/- 0.3% in controls. Plasma nicotine was 57 +/- 7 ng/ml and plasma cotinine was 590 +/- 23 ng/ml in nicotine-exposed animals and below detection levels in controls. CO exposure induced a 21% increase in right ventricular hypertrophy (p < 0.01), a 7% increase in left ventricular hypertrophy (p < 0.01), a 25% increase in right ventricular ET-1 expression (p < 0.05), and an eightfold increase in ANP expression (p = 0.08). ET(A) receptor antagonism reduced right ventricular hypertrophy by 60% (p < 0.05) with no significant effect on left ventricular hypertrophy or myocardial ET-1 expression. Chronic nicotine exposure did not significantly affect cardiac weights or ANP and ET-1 expression. We conclude that ET(A) receptor antagonism reduces right ventricular hypertrophy induced by chronic CO exposure, whereas CO-induced myocardial ET-1 expression remains unchanged.

Animals↗

PubMed2002

Neuroendocrine differentiation in gastric adenocarcinomas associated with severe hypergastrinemia and/or pernicious anemia.

Patients with hypergastrinemia secondary to achlorhydria have an increased risk of developing ECL cell carcinoids and gastric adenocarcinomas. Hypergastrinemia is central in the pathogenesis of ECL cell carcinoids, but the link between gastrin and gastric carcinomas is controversial. During neoplastic transformation ECL cells may, however, lose many of their neuroendocrine characteristics, making them difficult to recognise as neuroendocrine with conventional immunohistochemical techniques. Neuroendocrine differentiation was therefore examined in eight gastric adenocarcinomas found in seven patients with severe hypergastrinemia and/or pernicious anemia using a monoclonal antibody towards chromogranin A and immunohistochemistry without and with a sensitive signal amplification technique. The Sevier-Munger method was used as a more specific marker of ECL cells. Seven of the carcinomas contained scattered neuroendocrine tumour cells. When using signal amplification, an increase in the number of immunoreactive neoplastic cells was seen. In many tumours, clusters or confluent sheets of such cells were disclosed, suggesting a neuroendocrine and ECL cell origin. These tumours may therefore be ECL cell carcinomas and hypergastrinemia may thus be involved in the tumourigenesis.

Adenocarcinoma↗

PubMed2002

The cellular localization of the cholecystokinin 2 (gastrin) receptor in the stomach.

The role of the gastric acid secretagogues acetylcholine, gastrin and histamine has been debated for decades. Initially, the mast cell was considered the source of acid stimulatory histamine. Later, Håkanson & Owman (1969) showed that the entero-chromaffinlike (ECL) cell produces and stores histamine in several species, including rat and man. Kahlson et al. (1964) showed that food and gastrin stimulated oxyntic mucosal histamine synthesis and release, Berglindh et at. (1976) that histamine and cholinergics but not gastrin induced acid secretion in isolated oxyntic glands and parietal cells, and Rangachari (1995) that acetylcholine or gastrin released histamine in isolated mucosa. These findings suggested that gastrin stimulates acid secretion through release of ECL cell histamine. Studying simultaneous histamine release and acid secretion in isolated oxyntic mucosal cells, we found that gastrin stimulated acid secretion only in preparations releasing histamine. Moreover, in the isolated rat stomach, gastrin stimulated both histamine release and acid secretion. Maximal acid output was higher with histamine than with gastrin, and augmented by acetylcholine but not by gastrin. These findings strongly suggested that gastrin acts by releasing histamine. Finally, a fluorescein-labelled gastrin analogue bound to the ECL cell, not to the parietal or stem cell regions. This is interesting, recalling that gastrin has a potent and specific trophic effect on the ECL cell and only a general effect on all other oxyntic cell types. In conclusion, physiological observations are best explained by localising the CCK2 receptor only to the ECL cell, the other effects of gastrin on the gastric mucosa being secondary to the release of mediators from the ECL cell.

Animals↗

PubMed2002

Long-term safety of proton pump inhibitors: risks of gastric neoplasia and infections.

After Helicobacter pylori eradication was introduced and largely eliminated the need for maintenance therapy for peptic ulcer disease, gastroesophageal reflux disease (GERD) became the main indication for prolonged gastric acid inhibition. The drug effect on GERD depends on the degree of acid inhibition, thus the efficacious proton pump inhibitors are preferred. The proton pump inhibitors have few immediate side effects, the main concern being the profound hypoacidity and hypergastrinaemia they induce. In short-term, hypergastrinaemia causes rebound hyperacidity, possibly worsening GERD and reducing the efficacy of histamine H(2) blockers. In the long-term, hypergastrinaemia causes enterochromaffin-like cell hyperplasia and carcinoids. Since enterochromaffin-like cells may be important in gastric carcinogenesis, iatrogenic hypergastrinaemia may predispose to carcinoma. Gastric hypoacidity also increases gut bacterial infections, and the barrier function of acid against viral and prion infections requires further assessment.

Animals↗