Early Adaptive Changes Research Articles

MRNA cargo no longer on time

heart failure is the most important cause of death in the Western world, and numerous attempts have been undertaken to identify the origin of this disease. Cohn et al. ([1][1]) in 2000 defined cardiac remodeling leading to heart failure as “genome expression resulting in molecular, cellular and

Fasting induces a biphasic adaptive metabolic response in murine small intestine.

BackgroundThe gut is a major energy consumer, but a comprehensive overview of the adaptive response to fasting is lacking. Gene-expression profiling, pathway analysis, and immunohistochemistry were therefore carried out on mouse small intestine after 0, 12, 24, and 72 hours of fasting.ResultsIntestinal weight declined to 50% of control, but this loss of tissue mass was distributed proportionally among the gut's structural components, so that the microarrays' tissue base remained unaffected. Unsupervised hierarchical clustering of the microarrays revealed that the successive time points separated into distinct branches. Pathway analysis depicted a pronounced, but transient early response that peaked at 12 hours, and a late response that became progressively more pronounced with continued fasting. Early changes in gene expression were compatible with a cellular deficiency in glutamine, and metabolic adaptations directed at glutamine conservation, inhibition of pyruvate oxidation, stimulation of glutamate catabolism via aspartate and phosphoenolpyruvate to lactate, and enhanced fatty-acid oxidation and ketone-body synthesis. In addition, the expression of key genes involved in cell cycling and apoptosis was suppressed. At 24 hours of fasting, many of the early adaptive changes abated. Major changes upon continued fasting implied the production of glucose rather than lactate from carbohydrate backbones, a downregulation of fatty-acid oxidation and a very strong downregulation of the electron-transport chain. Cell cycling and apoptosis remained suppressed.ConclusionThe changes in gene expression indicate that the small intestine rapidly looses mass during fasting to generate lactate or glucose and ketone bodies. Meanwhile, intestinal architecture is maintained by downregulation of cell turnover.

Early adaptive changes in chronic paraplegic mice: a model to study rapid health degradation after spinal cord injury

Literature review. To describe quantitatively some of most important anatomic, systemic, and metabolic changes occurring soon (one month) after spinal cord trauma in mice. University Laval Medical Center. Significant changes in weight, mechanical and contractile muscle properties, bone histomorphometry and biomechanics, deep-vein morphology, complete blood count, immune cell count, lipid metabolism and anabolic hormone levels were found occurring within 1 month in completely spinal cord transected (Th9/10) mice. These data reveal that many changes in mice and humans are comparable suggesting, in turn, that this model may be a valuable tool for neuroscientists to investigate the specific mechanisms associated with rapid health degradation post-SCI.

Comparison of P2X and TRPV1 Receptors in Ganglia or Primary Culture of Trigeminal Neurons and their Modulation by NGF or Serotonin

BackgroundCultured sensory neurons are a common experimental model to elucidate the molecular mechanisms of pain transduction typically involving activation of ATP-sensitive P2X or capsaicin-sensitive TRPV1 receptors. This applies also to trigeminal ganglion neurons that convey pain inputs from head tissues. Little is, however, known about the plasticity of these receptors on trigeminal neurons in culture, grown without adding the neurotrophin NGF which per se is a powerful algogen. The characteristics of such receptors after short-term culture were compared with those of ganglia. Furthermore, their modulation by chronically-applied serotonin or NGF was investigated.ResultsRat or mouse neurons in culture mainly belonged to small and medium diameter neurons as observed in sections of trigeminal ganglia. Real time RT-PCR, Western blot analysis and immunocytochemistry showed upregulation of P2X3 and TRPV1 receptors after 1–4 days in culture (together with their more frequent co-localization), while P2X2 ones were unchanged. TRPV1 immunoreactivity was, however, lower in mouse ganglia and cultures. Intracellular Ca2+ imaging and whole-cell patch clamping showed functional P2X and TRPV1 receptors. Neurons exhibited a range of responses to the P2X agonist α, β-methylene-adenosine-5'-triphosphate indicating the presence of homomeric P2X3 receptors (selectively antagonized by A-317491) and heteromeric P2X2/3 receptors. The latter were observed in 16 % mouse neurons only. Despite upregulation of receptors in culture, neurons retained the potential for further enhancement of P2X3 receptors by 24 h NGF treatment. At this time point TRPV1 receptors had lost the facilitation observed after acute NGF application. Conversely, chronically-applied serotonin selectively upregulated TRPV1 receptors rather than P2X3 receptors.ConclusionComparing ganglia and cultures offered the advantage of understanding early adaptive changes of nociception-transducing receptors of trigeminal neurons. Culturing did not prevent differential receptor upregulation by algogenic substances like NGF or serotonin, indicating that chronic application led to distinct plastic changes in the molecular mechanisms mediating pain on trigeminal nociceptors.

Differential Display in Rat Livers Treated for 13 Weeks with Phenobarbital Implicates a Role for Metabolic and Oxidative Stress in Nongenotoxic Carcinogenicity

Hepatic enzyme inducers such as phenobarbital are often nongenotoxic rodent hepatocarcinogens. Currently, nongenotoxic hepatocarcinogens can only be definitively identified through costly and extensive long-term, repeat-dose studies (e.g., 2-year rodent carcinogenicity assays). Although liver tumors caused by these compounds are often not found to be relevant to human health, the mechanism(s) by which they cause carcinogenesis are not well understood. Toxicogenomic technologies represent a new approach to understanding the molecular bases of toxicological liabilities such asnongenotoxic carcinogenicity early in the drug discovery/development process. Microarrays have been used to identify mechanistic molecular markers of nongenotoxic rodent hepatocarcinogenesis in short-term, repeat-dose preclinical safety studies. However, the initial "noise" of early adaptive changes may confound mechanistic interpretation of transcription profiling data from short-term studies, and the molecular processes triggered by treatment with a xenobiotic agent are likely to change over the course of long-term treatment. Here, we describe the use of a differential display technology to understand the molecular mechanisms related to 13 weeks of dosing with the prototype rodent nongenotoxic hepatocarcinogen, phenobarbital. These findings implicate a continuing role for oxidative stress in nongenotoxic carcinogenicity.An Excel data file containing raw data is available in full at http://taylorandfrancis.metapress.com/openurl.asp?genre=journal&issn=0192-6233. Click on the issue link for 33(1), then select this article. A download option appears at the bottom of this abstract. The file contains raw data for all gene changes detected by AFLP, including novel genes and genes of unknown function; sequences of detected genes; and animal body and liver weight ratios. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org.

Human aortocoronary grafts and nitric oxide release: relationship to pulsatile pressure

Background. Short and long-term failure of saphenous vein grafts continues to be a significant problem for cardiac surgeons. The purpose of this study was to elucidate the early adaptive changes of human artery and vein conduits with respect to nitric oxide (NO) production under various pressure and pulsatile distention conditions.Methods. Real-time amperometric NO determinations were made in an in vitro model using human saphenous vein segments (n = 12) and internal thoracic artery segments (n = 8) between 70 and 170 mm Hg, under static conditions recorded with a pressure transducer. Exposing the tissue to morphine (10−6 M) also stimulated NO release. Under conditions in which the conduits were exposed to the respective pressures for 1 hour, they were then examined for their granulocyte-adhering potential using computer-assisted imaging techniques.Results. A pressure-dependent decrease of NO release was found after 32 minutes of pulsatile pressure (170 mm Hg) in artery and vein, the latter of which appeared to be affected more negatively (p < 0.05; because many more observation points differed significantly after 32 minutes compared to 110 mm Hg values). In vessels maintained for 1 hour at these different pressures and then exposed to morphine (1 μM), stimulated NO release significantly diminished in the veins (artery 37.4 nM NO versus vein 18.1 nM NO; p < 0.05). Increased pressures also correlated with an increase in granulocyte adhesion to veins that could not be reduced following morphine exposure.Conclusions. Increased pressure and cyclic distention lead to loss of NO release and increased immunocyte adhesion, which are significantly more pronounced in saphenous vein than in internal thoracic artery, suggesting that in the long term this may contribute to the failure of saphenous vein conduits in coronary revascularization.

Impaired glucose transporter activity in pressure-overload hypertrophy is an early indicator of progression to failure.

Severe hypertrophy and heart failure are important risk factors in cardiac surgery. Early adaptive changes in hypertrophy include increased ventricular mass-to-cavity volume ratio (M/V ratio) and increased dependence on glucose for energy metabolism. However, glucose uptake is decreased in the late stages of hypertrophy when ventricular dilatation and failure are present. We hypothesized that impaired glucose uptake would be evident early in the progression of hypertrophy and associated with the onset of ventricular dilatation. Ten-day-old rabbits underwent banding of the descending aorta. Development of hypertrophy was followed by transthoracic echocardiography to measure left ventricular M/V ratio. Glucose uptake rate, as determined by (31)P-nuclear magnetic resonance spectroscopy measuring 2-deoxyglucose conversion to 2-deoxyglucose-6-phosphate, was measured in isolated perfused hearts obtained from banded rabbits when M/V ratio had increased by 15% from baseline (compensated hypertrophy) and by 30% from baseline (early-decompensated hypertrophy). In age-matched control animals, the rate of glucose uptake was 0.61+/-0.08 micromol x g of wet weight(-1) x 30 min(-1) (mean+/-SEM). With a 15% M/V ratio increase, glucose uptake rate remained at control levels (0.6+/-0.05 micromol x g of wet weight(-1) x 30 min(-1)), compared with hearts with 30% increased M/V ratios, where glucose uptake was significantly lower (0.42+/-0.05 micromol x g of wet weight(-1) x 30 min(-1); P</=0.05). Glucose transporter protein expression was the same in all groups. Glucose uptake rate is maintained during compensated hypertrophy. However, coinciding with severe hypertrophy, preceding ventricular dilatation, and glucose transporter protein downregulation, glucose uptake is significantly decreased. Because of the increased dependence of the hypertrophied hearts on glucose use, we speculate that this impairment may be a contributing factor in the progression to failure.

Impaired Glucose Transporter Activity in Pressure-Overload Hypertrophy Is an Early Indicator of Progression to Failure

Background —Severe hypertrophy and heart failure are important risk factors in cardiac surgery. Early adaptive changes in hypertrophy include increased ventricular mass-to-cavity volume ratio (M/V ratio) and increased dependence on glucose for energy metabolism. However, glucose uptake is decreased in the late stages of hypertrophy when ventricular dilatation and failure are present. We hypothesized that impaired glucose uptake would be evident early in the progression of hypertrophy and associated with the onset of ventricular dilatation. Methods and Results —Ten-day-old rabbits underwent banding of the descending aorta. Development of hypertrophy was followed by transthoracic echocardiography to measure left ventricular M/V ratio. Glucose uptake rate, as determined by 31 P-nuclear magnetic resonance spectroscopy measuring 2-deoxyglucose conversion to 2-deoxyglucose-6-phosphate, was measured in isolated perfused hearts obtained from banded rabbits when M/V ratio had increased by 15% from baseline (compensated hypertrophy) and by 30% from baseline (early-decompensated hypertrophy). In age-matched control animals, the rate of glucose uptake was 0.61±0.08 μmol · g of wet weight −1 · 30 min −1 (mean±SEM). With a 15% M/V ratio increase, glucose uptake rate remained at control levels (0.6±0.05 μmol · g of wet weight −1 · 30 min −1 ), compared with hearts with 30% increased M/V ratios, where glucose uptake was significantly lower (0.42±0.05 μmol · g of wet weight −1 · 30 min −1 ; P ≤0.05). Glucose transporter protein expression was the same in all groups. Conclusions —Glucose uptake rate is maintained during compensated hypertrophy. However, coinciding with severe hypertrophy, preceding ventricular dilatation, and glucose transporter protein downregulation, glucose uptake is significantly decreased. Because of the increased dependence of the hypertrophied hearts on glucose use, we speculate that this impairment may be a contributing factor in the progression to failure.

Early adaptive changes in neurohormonal control of the rat exocrine pancreas with 7 days of chronic alcohol ingestion

Early adaptive changes in neurohormonal control of the rat exocrine pancreas with 7 days of chronic alcohol ingestion

Binocular interactions in rapid saccadic adaptation

An adaptive mechanism controls the strength of innervation to the two eyes independently. However, under some circumstances an adjustment in strength of innervation to one eye is generalized to the other. The coupling and uncoupling of the two eyes during saccadic motor learning was studied using the technique of intrasaccadic target displacements to provide a precise visual-motor error proportional to the commanded movement. Early adaptive changes (saccade plus fast vergence) were measured within the saccadic interval and late adaptive changes (vergence error) were measured after the saccadic interval. When one viewing eye was retrained using intrasaccadic displacements, saccadic amplitude changes generalized to the other nonviewing eye. Thus, rapid adaptive changes trained monocularly were transferred to the nonviewing eye. But when two eyes were viewing and an adaptive stimulus was provided to only one eye (binocular viewing-monocular training), adaptive changes also occurred in both eyes. Experiments described here suggest that the recalibration of the saccade occurs quickly as a conjugate adjustment of gain which is used to balance innervation to the two eyes. Thereafter, disconjugate mechanisms provide a further recalibration to each eye independently.

Effects of ten-day aerobic training on the energy potential and blood supply of skeletal muscle in rats

The activity of mitochondrial creatine kinase is found to increase in skeletal muscles of rats after ten days of running a treadmill. Over that short period, however, no significant increases occur either in the maximal rate of mitochondrial respiration or in the number of capillaries per skeletal muscle fiber and their density, nor are the early adaptive changes in muscle tissue accompanied by modifications in the resistive or metabolic compartments of the vascular bed, i.e. by improvements in the blood supply to muscle tissue.

Early ultrastructural adaptive changes of ileal enterocytes after proximal small bowel resection as determined morphometrically.

The aim of the present study was to evaluate in terms of quantitative measurements whether the well-known histomorphological and functional adaptive changes in the intestinal mucosa after small bowel resection are accompanied by alterations on the ultrastructural level. Therefore, samples of the ileal remnants after a 60% proximal resection were processed for ultrastructural evaluation and analyzed employing point counting planimetry and direct measurements. Microvillus surface area increased from the bottom of the crypts to the villus tips in both resected and sham-operated animals. This increase in microvillus surface area from the crypt to the villus was significantly less pronounced after proximal resection, while there were no changes in the crypt compartment. No significant differences of the relative areas of the nuclei, mitochondria, and the rough endoplasmic reticulum were observed when comparing the different positions along the villus crypt axis in normal and hyperplastic mucosa. In agreement with functional and enzyme histochemical results, these ultrastructural findings provide further evidence for an altered pattern of enterocyte maturation after proximal resection, which is most probably due to an increase in the migration rate of the enterocytes.

Gastric stapling for morbid obesity: gastrointestinal response in a rat model

The adaptive response of the gastrointestinal tract to gastric stapling was studied in a Zucker (fafa) genetically obese rat model. The effects of gastric stapling in rats with a Roux-en-Y gastrojejunostomy were compared to Roux-en-Y and intact controls. Rats (225 to 275 g) were divided into three groups: group I (GI), Roux-en-Y, stapled, ad libitum fed; group II, Roux-en-Y, unstapled; and group III, intact (laparotomy only). Groups II and III were further subdivided into group IIA (GIIA) and group IIIA (GIIIA), pair-fed to GI; and group IIB (GIIB) and Group IIIB (GIIIB), fed ad libitum. All rats were fed a diet of liquid rat formula and rat food (50:50 cal ratio). After 2 wk rats were killed and the liver, pancreas, and stomach removed, weighed, and tissue taken for histology. The intestine was divided into three segments corresponding to the excluded segment (1, duodenum), transposed segment (2, jejunum), and ileal segment (3), with tissue taken for histology. Liver lipid, pancreatic amylase, serum amylase and gastrin, and intestinal mucosal protein and DNA were measured. Weight gain, g/14 days, was: GI, 24.1 ± 7.8; GIIA, 17.0 ± 2.0; GIIB, 42.6 ± 4.8; GIIIA, 17.6 ± 4.7; GIIIB, 54.6 ± 8.9. All rats were in positive N balance. Liver weight and lipid were similar in all groups. Pancreatic mass was significantly increased in all Roux-en-Y animals, while amylase activity per g tissue was significantly less than in intact animals. Stapled rats had atrophy of the glandular portion of the stomach, decreased stomach mucosal weight, and lower serum gastrin concentration compared with all other rats (p < 0.01). In stapled rats, segment weight and mucosal weight were lower in the excluded segment, and higher in the transposed segment, compared to all other rats. Tissue pathology was found only in stapled rats: gastric atrophy, focal fibrosis of gastric wall, peritonitis, minimal to mild multifocal hepatitis, and mild periductal fibrosis of the pancreas. There are significant early adaptive and pathological changes after gastric stapling in the rat.

Aerodynamic characteristics of the early stages of speech adaptation to a dental appliance

Sibilants, especially /s/, present the greatest difficulty in speech adaptation to a dental appliance. The flow profile for /s/ in an intervocalic context is double humped, reflecting the dynamic interplay between vocal fold opening and tongue gesture. Air-flow profiles for /s/ during the first few minutes of adaptation show a marked change (either much higher or much lower) compared to a compensated condition two weeks later. These flow profiles were also more variable than in the compensated condition—the greatest contribution stemming: from the very first reading of the speech sample. Successive readings showed continued, but more gradual, adjustments. Consideration is given to alterations in timing of articulatory gestures as the mechanism producing these early adaptive changes. [Work supported by NIH.]