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At least 253 records · Page 14Linked to original sources

PubMed2003

Cerebrovascular pressure reactivity is related to global cerebral oxygen metabolism after head injury.

BACKGROUND: After head injury, impaired cerebrovascular autoregulation has been associated with abnormally high or low cerebral blood flow. The physiological relevance of cerebral blood flow levels is difficult to assess in these patients, whose cerebral metabolic rate for oxygen (CMRO(2)) is known to be abnormal. Investigation of these relations requires quantitative measures of cerebral blood flow and CMRO(2), to allow assessment of oxygen supply and demand relations. OBJECTIVES: To investigate the relation between dysautoregulation and global cerebral oxygen metabolism following head injury. METHODS: Using positron emission tomography, global cerebral blood flow, CMRO(2), and oxygen extraction fraction were determined in 22 patients who were investigated in 26 examinations on days 1 to 11 (mean (SD), 3.5 (2.3)) after head injury. Cerebrovascular pressure reactivity was assessed using a pressure reactivity index, calculated as the moving linear correlation coefficient between mean arterial blood pressure and intracranial pressure. Outcome was assessed six months after injury using the Glasgow outcome scale. RESULTS: Low CMRO(2) was associated with disturbed pressure reactivity (inverse function, R(2) = 0.21, p = 0.018) and there was a correlation between disturbed pressure reactivity and oxygen extraction fraction (quadratic function, R(2) = 0.55, p = 0.0001). There was no significant relation between pressure reactivity and cerebral blood flow. An unfavourable outcome was associated with disturbed pressure reactivity. There was no significant relation between outcome and CMRO(2) or oxygen extraction fraction. CONCLUSIONS: There is a close relation between dysautoregulation and abnormal cerebral metabolism but not blood flow. Further studies are needed to determine whether metabolic dysfunction is a result of or a cause of disturbed pressure reactivity, and to establish if there is a relation between cerebral oxygen metabolism and outcome.

Adolescent↗

PubMed2002

Adult polycystic ovary syndrome begins in childhood.

Polycystic ovary syndrome (PCOS) frequently presents during adolescence and is the commonest cause of menstrual irregularity and hirsutism. The characteristic endocrine abnormalities include hypersecretion of androgens and LH. Metabolic dysfunction is also a feature of many young women with PCOS. Hyperinsulinaemia and insulin resistance, which can be regarded as an exaggeration of the normal metabolic changes that occur during puberty, are further amplified by obesity. The aetiology of PCOS is uncertain but there is evidence for a primary abnormality of ovarian androgen production which is manifest at puberty but may have its origins in childhood or even during fetal development.

Adolescent↗

PubMed1993

Recovery of regional contractile function and oxidative metabolism in stunned myocardium induced by 1-hour circumflex coronary artery stenosis in chronically instrumented dogs.

Stunned myocardium produced by 1 hour of critical coronary artery stenosis was evaluated for alteration in regional mechanical function and overall oxidative and fatty acid metabolism by positron emission tomography (PET) in chronically instrumented dogs. Twenty-seven dogs, chronically instrumented for measurements of left ventricular pressure and regional myocardial wall thickening in normal and ischemic zones, were subjected to a 1-hour period of myocardial ischemia produced by graded left circumflex coronary artery stenosis, resulting in minimal residual flow. Mean transmural myocardial flow during 1-hour coronary stenosis decreased to 0.34 +/- 0.04 ml/min per gram in the ischemic zones (normal zone transmural flow, 0.96 +/- 0.10 ml/min per gram). Systolic wall thickening in the ischemic zone was almost completely abolished (-97 +/- 4%). On reperfusion, systolic wall thickening immediately resumed but remained depressed. Progressive recovery was noted with time. At 24 hours, systolic wall thickening was still depressed (-20 +/- 6%, p < 0.01). At 1 week, wall thickening had completely recovered and was no longer significantly different from the control condition. In addition, the absence of necrosis at the site of wall thickness measurements was confirmed at autopsy in all dogs. No abnormalities were found by electron microscopy in four dogs undergoing myocardial biopsies at the time of PET studies. Dynamic PET studies using [1-11C]acetate tracer (performed at 6 hours, 1 week, and 2 weeks after reperfusion) and [1-11C]palmitic acid tracer (performed at 6 hours, 12 hours, 24 hours, 1 week, and 2 weeks after reperfusion) allowed the computation of regional tissue time-activity curves in different regions of interest at different times during follow-up. Despite full reperfusion, abnormal [1-11C]acetate and [1-11C]palmitic acid kinetics were observed in the posterior segments, previously subjected to ischemia, as evidenced by a significant decrease in the slope of the early 11C clearance curve component. Repeat PET studies revealed progressive normalization of overall oxidative metabolism and fatty acid metabolism, which paralleled the time course of recovery of mechanical function. Thus, myocardial ischemia, produced by 1-hour coronary artery stenosis, followed by full reperfusion is associated with a prolonged period of postischemic mechanical and metabolic dysfunction. This transient reduction in oxygen delivery induced a prolonged impairment in fatty acid beta-oxidation as well as a reduction in overall oxidative metabolism despite full reoxygenation. A similar time course for recovery of function and metabolism was observed.

Acetates↗

PubMed2000

1H-MR spectroscopic monitoring of posttraumatic metabolism following controlled cortical impact injury: pilot study.

Proton magnetic resonance spectroscopy (1H-MRS) has been increasingly utilised in experimental traumatic brain injury for characterisation of posttraumatic metabolic dysfunction. Following human brain injury pathological findings correlated with outcome measures. Combined with conventional T2-weighted MR imaging MRS is a sensitive tool to evaluate metabolic changes in brain tissue following trauma. Studies have been restricted so far to diffuse axonal injury models and fluid percussion injury. Using a high resolution scanner at 4.7 T, MRI combined with 1H-MRS was applied in a pilot study to the controlled cortical impact injury model of experimental brain contusion (CCII). Eight Sprague-Dawley rats were investigated, of which two served as controls. Four animals were injured 24 h after craniotomy, two investigated at 72 h post craniotomy. MRS/MRI indicated a transient brain oedema development and metabolic changes induced by the craniotomy itself. Following CCII MRI demonstrated that the area of contusion as well as the surrounding brain oedema increased twofold in size within 24 h (p < 0.05). MRS showed an immediate increase of N-acetylaspartate (NAA) and glutamate ipsilateral to the contusion and a drop of NAA on the contralateral side. MRS/MRI investigations in the CCII model demonstrated a potential to further elucidate the pathophysiology following traumatic brain contusion.

Animals↗

PubMed2002

Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy.

Mutations of the human plectin gene (Plec1) cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). Here, we report on molecular mechanisms leading to severe dystrophic muscle alterations in EBS-MD. Analysis of a 25-yr-old EBS-MD patient carrying a novel homozygous 16-bp insertion mutation (13803ins16/13803ins16) close to the intermediate filament (IF) binding site of plectin showed severe disorganization of the myogenic IF cytoskeleton. Intermyofibrillar and subsarcolemmal accumulations of assembled but highly unordered desmin filaments may be attributed to impaired desmin binding capability of the mutant plectin. This IF pathology was also associated with severe mitochondrial dysfunction, suggesting that the muscle pathology of EBS-MD caused by IF disorganization leads not only to defects in mechanical force transduction but also to metabolic dysfunction. Beyond EBS-MD, our data may contribute to the understanding of other myopathies characterized by sarcoplasmic IF accumulations such as desminopathies or alpha-B-crystallinopathies.

Adult↗

PubMed1994

Neuroimaging in infantile autism.

Metabolic findings using [18F]fluorodeoxyglucose (FDG) with positron emission tomography (PET) and correlative anatomic findings with computed tomography (CT) or magnetic resonance imaging (MRI) were characterized in 13 children with infantile autism. Four of 13 patients had both an abnormal FDG-PET and an abnormal MRI, whereas seven of 13 patients had both a normal FDG-PET and a normal CT or MRI. Sixteen of a total of 195 brain areas qualitatively examined with FDG-PET had a hypometabolic abnormality on PET. Three of the five abnormal structural imaging studies revealed neuronal migrational anomalies (focal pachygyria). In two of the five patients with anatomic abnormalities, these were noted only after knowledge of the FDG-PET findings. Our experience reveals that anatomic and metabolic abnormalities can be found in children who exhibit autistic behavior. An FDG-PET study may provide evidence of metabolic dysfunction after an initially unremarkable MRI scan because subtle anatomic abnormalities (as those seen with neuronal migrational anomalies) may be found only after knowledge of a regional metabolic abnormality.

Autistic Disorder↗

PubMed2026

Cryopreservation-induced proteomic alterations in Pêga donkey (Equus asinus) spermatozoa.

Semen cryopreservation is a key tool for assisted reproduction and genetic conservation, but its efficiency remains limited in donkeys, compromising post-thaw sperm quality. This study aimed to characterize the proteomic profile of Pêga donkey spermatozoa and to investigate molecular mechanisms associated with cryopreservation-induced impairment of sperm function. Semen samples were collected from Pêga jacks and evaluated for sperm motility and vigor before and after cryopreservation. Quantitative proteomic analysis was performed by LC-MS/MS, followed by bioinformatic characterization of differentially abundant proteins. Cryopreservation markedly reduced sperm motility in all animals, whereas sperm vigor showed only a non-significant tendency toward reduction, suggesting sublethal cryoinjury primarily affecting flagellar efficiency. Proteomic profiling identified 554 proteins, of which 98 were differentially abundant between in natura and cryopreserved spermatozoa. Functional enrichment analyses showed that these proteins were mainly associated with energy metabolism, mitochondrial oxidative phosphorylation, glycolysis, cytoskeletal organization, signal transduction, proteostasis, and oxidative stress response. Notably, proteins involved in ATP production, mitochondrial function, and axonemal organization were significantly altered, supporting a mechanistic link between metabolic dysfunction, flagellar structural disorganization, and reduced post-thaw motility. Overall, cryopreservation induced coordinated and compartment-specific remodeling of the donkey sperm proteome, particularly affecting pathways essential for motility and functional competence. These findings provide new molecular insights into the cryobiological vulnerability of donkey spermatozoa and establish a mechanistic basis for the development of more effective, biology-driven cryopreservation strategies for this species.

Animals↗

PubMed1988

Differential effects of distal and proximal nerve lesions on carbonic anhydrase activity in rat primary sensory neurons, ventral and dorsal root axons.

The effect of proximal and distal peripheral nerve injuries on the histochemistry of carbonic anhydrase (CA) in rat dorsal root ganglion (DRG) neurons, and myelinated (MyF) dorsal and ventral root fibers was studied. Sciatic neurectomy induced no change. Contrariwise, 7 days after lumbar spinal nerve section the numbers of CA-stained ventral root MyF and DRG cells at the L4 and L5 levels decreased to 73.2% and 51.9% of their original values respectively, although the numbers returned to normal by the 90th postoperative day. Dorsal root MyF followed a similar trend, albeit with some delay. Major morphological changes comprised atrophy of dorsal root sensory neurons and axons, particularly in long term experiments, as well as nuclear eccentricity in DRG neurons. These results suggest that, depending on the site of lesion, the rat peripheral nervous system (PNS) either maintains or quickly restores its capacity to synthesize CA. They stand in contrast to the long-lasting metabolic dysfunctions reported to occur when primary neurons are disconnected from the periphery. It is uncertain whether this difference is due to the critical role of CA in neuronal metabolism.

Animals↗

PubMed1981

Effects of thyroid dysfunction on the metabolism of halothane, enflurane and methoxyflurane in rats.

The effect of thyroid dysfunction on the metabolism of halothane (100 ppm), enflurane (100 ppm) and methoxyflurane (300 ppm) was investigated during application by inhalation. In male rats the elimination half-lives from the atmosphere of the exposure system amounted to 0.76h for halothane, 6.84h for enflurane and 0.64h for methoxyflurane. Hyperthyroidism due to three daily injections of 0.1 mg/kg triiodothyronine i.p. significantly shortened the half-lives of all three inhalation anesthetics. Hypothyroidism due to operative removal of the thyroid gland affected the metabolism of halothane only as evidenced by a prolongation of the elimination half-life while enflurane and methoxyflurane half-lives remained unchanged. The observed differences in metabolic rates are explained by different metabolic pathways of the three compounds. They may be important for the manifestation of toxic effects.

Animals↗

PubMed2003

Focal hypoxia of the obstructed rabbit bladder wall correlates with intermediate decompensation.

AIMS: We showed that partial obstruction of the rabbit bladder outlet caused decreases in detrusor blood flow that were directly proportional to the level of decompensation present. Bladder decompensation is characterized by decreases in detrusor contractility, mitochondrial function, and sarco/endoplasmic reticulum calcium ATPase (SERCA) activity in obstructed rabbits. The current study was designed to create bladder decompensation and to relate its characteristic dysfunctions to the presence or absence of hypoxia in the obstructed rabbit bladder wall. Tissue hypoxia was visualized immunohistochemically after administration of a hypoxia probe in vivo. METHODS: Twelve New Zealand White rabbits were separated into two groups. The rabbits in group 1 received sham operations; the rabbits in group 2 received partial outlet obstructions by standard methods. Four weeks after surgery, each rabbit received an intraperitoneal injection of aqueous Hypoxyprobe-1, which forms protein adducts in cells having O(2) concentrations less than 14 microM. Two hours after injection, the rabbit was anesthetized and the bladder exposed through a midline incision. One full-thickness bladder strip was cut and immediately placed in fixative for immunohistochemical recognition and visualization of Hypoxyprobe-1-protein adducts. The remaining bladder was then excised, and three additional strips were cut for contractility studies. The remainder of the bladder was frozen for biochemical and slot-blot analyses. RESULTS: Bladder weight was increased fourfold after obstruction, and significant contractile and biochemical dysfunctions were observed that indicated an intermediate level of decompensation. Immunohistochemical visualization revealed focal areas of moderate to severe hypoxia in the detrusor smooth muscle (SM) and subserosal regions of these bladders. No hypoxia was observed in the obstructed bladder mucosa, consistent with the absence of biochemical dysfunction in this compartment, or in unobstructed bladders. Slot-blot analyses confirmed the presence of significant Hypoxyprobe-1-protein adducts in the detrusor of the obstructed bladder, whereas none were present in the control bladder detrusors. CONCLUSIONS: Partial outlet obstruction of rabbit bladders resulted in focal areas of moderate to severe hypoxia in the detrusor SM and subserosal regions concomitant with increased bladder mass, decreased contractile function, and selective metabolic dysfunctions of the SM consistent with an intermediate stage of decompensation. The metabolic characteristics of the normoxic mucosa were normal a were those of unobstructed bladders.

Adenosine Triphosphate↗

PubMed1995

Mitochondrial deoxyribonucleic acid content is specifically decreased in adult, but not fetal, pancreatic islets of the Goto-Kakizaki rat, a genetic model of noninsulin-dependent diabetes.

Considerable interest has recently been focused on the putative role of mutations in the mitochondrial genome for the development of noninsulin-dependent diabetes. The Goto-Kakizaki (GK) rat, a genetic model of defective insulin secretion and hyperglycemia, is characterized by partial maternal inheritance. Because the mitochondrial genome is known to be maternally transmitted, the aim of this study was to investigate whether the GK syndrome can be explained in terms of alterations of the mitochondrial DNA (mtDNA). For this purpose, pancreatic islets were isolated from adult and fetal control Wistar and diabetic GK rats. Using electron microscopy, the ultrastructural morphology of beta-cell mitochondria was analyzed in control and GK islets. It was found that the beta-cells of adult GK rats had a significantly smaller mitochondrial volume and an increased number of mitochondria per unit tissue volume as compared with the beta-cells of corresponding control islets. Moreover, mtDNA and mtRNA were isolated from the islets and, as a control tissue, from liver, and subsequently analyzed using Southern and Northern blot techniques. No major deletions or restriction fragment polymorphism could be detected in mtDNA from both GK liver and GK islets. The mtDNA sequence of the transfer RNAleu(UUS) gene was identical in both strains of rats. mtDNA contents of fetal GK islets and fetal GK liver were not different from those of fetal Wistar rats. However, adult GK islets contained markedly less mtDNA than the corresponding control islets, contrary to the mtDNA contents of adult liver, which were similar in the two strains. The lower islet mtDNA contents were paralleled by a decreased content of islet mtRNA (12S ribosomal RNA and cytochrome b messenger RNA). Islet insulin messenger RNA contents were similar in GK and Wistar rats. In conclusion, our results do not support a role of a genetic defect in mtDNA as a cause of the GK syndrome. Instead, mtDNA damage may occur specifically in islet cells as a consequence of the disturbed metabolic environment of the adult GK rat. It is speculated that a long-lasting metabolic dysfunction may induce mtDNA damage and/or inhibition of mtDNA replication leading to a gradual and late decrease in the mitochondrial volume fraction and subsequently an impaired capacity for oxidative metabolism.

Animals↗

PubMedDate not supplied

The role of mineral metabolism and inflammation on dialysis vascular access failure.

Thrombosis of arteriovenous fistula (AVF) is the leading cause of vascular access (VA) loss usually due to silent stenosis. Therefore, assessment of relevant risk factors of VA monitoring may provide insight into potential therapeutic targets for stenosis and thrombosis. The aim of this study was to evaluate the influence of cardiovascular risk factors (including inflammation and mineral metabolism dysfunctions) on the failure of internal AVF in HD patients. 128 HD patients with internal AVF were included in the study and followed up for two years. At baseline, VA morphology and function were followed by Doppler ultrasonography and serum albumin, prealbumine, C-reactive protein, orosomucoid, calcium, phosphorus, parathyroid hormone, bone-type alkaline phosphatase, osteoprotegerin and receptor activator of nuclear factor ê ê B ligand were measured. At baseline, 50 stenoses were detected but none of them required any intervention. Age and biological parameters did not significantly differ between patients with or without VA stenosis. Over the two year- follow up, VA thrombosis occurred in 19 patients. Preexisting stenosis of VA was present in 9/19 patients (47.3% of cases) (chi-square = 3.708, p = 0.0538). Despite the low rate of events, phosphorus [1.75 (0.95-2.77) vs 1.42 (0.47-3.22) mmol/L, p = 0.0416], Calcium x Phosphorus product [4.00 (2.00-5.90) vs 3.40 (1.10-6.80) mmol(2)/L(2), p = 0.0676] and parathyroid hormone [165.00 (1.00-944.00) vs 79.50 (1.00-846.60) ng/L, p = 0.0814) levels were higher in the 19 thrombotic patients whereas all other biological parameters did not significantly differ. These results, which confirm that VA thrombosis occurs more frequently upon preexisting stenosis, also demonstrate that mineral metabolism disorders, compared to inflammation, may contribute to VA dysfunction leading to thrombosis.

Adult↗

PubMed2006

Physical activity, fitness and cardiovascular disease risk in adults: interactions with insulin resistance and obesity.

There is a considerable body of evidence gathered from studies over the past half a century indicating that a high level of physical activity and a moderately high or high degree of cardiorespiratory fitness reduces the risk of CVD (cardiovascular disease). Recent data suggest that high levels of physical activity or fitness may be particularly beneficial to individuals with insulin-resistant conditions, such as the metabolic syndrome, Type II diabetes or obesity. These individuals, if unfit and sedentary, exhibit increased CVD risk, but their dose-response relationship for physical activity/fitness appears to be particularly steep such that, when they undertake high levels of activity (or have high fitness), their level of risk becomes closer to that of their normal weight or nondiabetic peers. This may be due to effects of physical activity in normalizing the metabolic dysfunction particularly associated with insulin-resistant conditions.

Cardiovascular Diseases↗

PubMed2002

[13C]aminopyrine and [13C]caffeine breath test: influence of gender, cigarette smoking and oral contraceptives intake.

The [13C]aminopyrine breath test ([13C]ABT) measures the global activity of cytochrome P450 in vivo and is a sensitive indicator of liver metabolic dysfunction. The present study aims to determine whether gender and cigarette smoking influence the results of [13C]ABT as well as to confirm the effect of oral contraceptive steroids (OCS) intake on this metabolic test. Hundred and ten healthy subjects, including men and women, smoker and non-smoker, women taking OCS or not, were phenotyped for CYP1A2 using the [13C]caffeine breath test and underwent a [13C]ABT. Both tests showed large inter-individual variations in accordance with that of CYP450 liver content. [13C]ABT was sensitive enough to point out a significant induction or inhibition related to cigarette smoking habits or OCS. The combined effect of smoking and OCS resulted in an overall unchanged metabolic activity. Consequently, the impact of the studied conditions on the [13C]ABT parameters must be considered by clinicians or clinical investigators.

Aminopyrine↗

PubMed1992

The lysosomal system in neurons. Involvement at multiple stages of Alzheimer's disease pathogenesis.

Disturbed lysosomal function may be implicated at several stages of Alzheimer's pathogenesis. Lysosomes and acid hydrolases accumulate in the majority of neocortical pyramidal neurons before typical degenerative changes can be detected, indicating that altered lysosome function is among the earliest markers of metabolic dysfunction in Alzheimer's disease. These early alterations could reflect accelerated membrane and protein turnover, defective lysosome or hydrolase function, abnormal lysosomal trafficking or any combination of these possibilities. Because APP is partly metabolized in lysosomes, early disturbances in lysosomal function could promote the production of abnormal and/or neurotoxic APP fragments within intact cells. Lysosomal abnormalities progressively worsen as neurons begin to degenerate. Based on existing literature on cell death, increased perturbation and instability of the lysosomal system may be expected to contribute to the atrophy and eventual lysis of the neuron. Finally, the release of hydrolase-filled lysosomes and lipofuscin aggregates from dying neurons accounts for the abundant deposition of enzymatically active acid hydrolases of all classes in the extracellular space--a phenomenon that may be unique to Alzheimer's disease. Acting on APP present in surrounding dystrophic neurites, cellular debris and astrocyte processes, dysregulated hydrolases may cleave APP in atypical sequential patterns, thereby generating self-aggregating protease-resistant APP fragments that can be only processed to beta-amyloid. Genetic mutations or posttranslational factors of APP should further enhance the generation of amyloidogenic fragments by a dysregulated lysosomal system. Given that very little, if any, beta-amyloid is detected intracellularly, yet extracellular beta-amyloid is very abundant, our data suggest that the final steps of APP processing and the generation of most beta-amyloid in the brain parenchyma occur extracellularly and may involve one or more lysosomal proteases.

Adolescent↗

PubMed2002

[Prenatal control related to the number of consultations as hyperglycemia diagnostic method].

INTRODUCTION: The impaired in the metabolism of the carbohydrates in a previously healthy woman who develops hyperglycemia during the pregnancy is know as gestational diabetes, the maternal-fetal mortality and morbility is almost the same one that a pregnant normal woman, if the metabolic dysfunction is appropriately controlled, the complications can be treated with success if the pregnant one attends prenatal control. OBJECTIVE: The aim of this study was to know the relationship between number of consultations and the hyperglycemia frequency to settle down. METHODS: 304 pregnant patients were studied that who request childbirth attention at emergency room of the gynecology and obstetrics service were studied; two groups were formed. The first group, 176 patients with term pregnancy in inadequate control with four or less prenatal consultations. The second group, 128 patients with five or more prenatal consultations. All had a fast of at least 4 hours, to take them a sample of blood and to determine the glucose during their entrance with initial childbirth labor. RESULTS: There was difference in the number of consultations that received each group with 1.4 +/- 1.0 consultations for the irregular group and 6.5 +/- 1.1 for the group with regular control. The pregnant ones with no prenatal consultation presented the biggest hyperglycemia percentage, but this percentage diminished as the pregnant ones attended to a bigger number of consultations, since they were detected the dysfunction of glucose on time and they could be treated appropriately. The glycemia was normal in all the patients that had more than 6 prenatal consultations because hyperglycemia was detected in 55 (31.2%) patients of the group with irregular prenatal control, in comparison with 4 (3.1%) of those with appropriate control (p < or = 0.001). CONCLUSION: It is shown that pregnant ones without an appropriate prenatal control with a smaller number of prenatal consultations, they have the biggest hyperglycemia percentage, because it was not possible to detect this dysfunction in an opportune way, this situation demonstrates the importance of identifying the causes of the faulty prenatal control, as well as to identify risk factors for the development of impaired in the metabolism of the carbohydrates.

Adult↗

PubMed1995

Use of mathematical models for predicting the metabolic effect of large-scale enzyme activity alterations. Application to enzyme deficiencies of red blood cells.

There are numerous examples showing that the metabolism of cells can be severely impaired if the activity of only one of the participating enzymes undergoes large-scale alterations, resulting, for example, from spontaneous mutations (inherited or acquired enzymopathies), the administration of toxic drugs or self-inactivation of enzymes during cell aging. However, a quantitative relationship between the degree of enzyme deficiency and the extent of metabolic dysfunction is very difficult to establish by experimental means. An alternative is to tackle this problem by mathematical modelling. Our approach is based on a comprehensive mathematical model of the energy and redox metabolism for human erythrocytes. We calculate stationary states of the cell metabolism, varying the activity of each of the participating enzymes by several orders of magnitude. The metabolic states are then evaluated in terms of a performance function which relates the metabolic variables to the overall functional fitness of the cell. The performance function for the erythrocyte takes into account the homeostasis of three essential metabolic variables: the energetic state (ATP), the reductive capacity (reduced glutathione), and the osmotic state. Based on the behaviour of the performance function at varying enzyme activities, we estimate those ranges of enzyme activities, in which the metabolic alterations should be either tolerable, associated with non-chronic or chronic diseases, or lethal. For most enzymopathies, the experimental and clinical observations can be satisfactorily rationalized by the computational results. Moreover, a surprisingly high correlation is found between the range of the activity range where disease is predicted by the model and the observed number of diseased probands. Another objective of our study was to contribute to the theory of metabolic control. The well-elaborated concept of the metabolic control theory is restricted to (infinitely) small activity alterations. In order to quantify the metabolic effect of finite (large-scale) changes in the activity of an enzyme, we propose, as a control measure, the effective activity E alpha, defined as the relative activity of an enzyme (with respect to the activity in a reference state) required to bring about a change in the stationary value of a metabolic variable by the (finite) factor alpha. We demonstrate that none of the existing extrapolation methods using the conventional control coefficient is capable to provide reliable predictions of the effective activities for all enzymes of erythrocyte metabolism.

Adenosine Triphosphate↗

PubMed2006

IL-1beta-induced iNOS expression, NO release and loss in metabolic cell viability are resistant to inhibitors of ceramide synthase and sphingomyelinase in INS 832/13 cells.

CONTEXT: Emerging evidence indicates regulatory roles for ceramide in the metabolic dysfunction of the islet beta cell. Recently, potential similarities between IL-1beta and ceramide on their effects on islet beta cell have been reported, including reduction in mitochondrial membrane potential and loss in metabolic cell viability. OBJECTIVE: Herein, we investigated whether IL-1beta-induced nitric oxide synthetase (iNOS) expression, nitric oxide (NO) release and loss in metabolic cell viability require ceramide biosynthesis either via the activation of sphingomyelinase or ceramide synthase. SETTING: Insulin-secreting INS 832/13 cells. RESULTS: We found that two structurally-distinct inhibitors of sphingomyelinase activation (e.g., 3-O-methylsphingomyelin or desipramine) or ceramide biosynthesis inhibitor (e.g., fumonisin) failed to exert clear effects on IL-1beta-induced iNOS expression, NO release and loss in cell viability. CONCLUSIONS: Taken together, our findings indicate that neither the sphingomyelinase nor the ceramide synthase activation is required for IL-1beta-induced metabolic abnormalities in insulin-secreting INS 832/13 cells.

Animals↗