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PubMed1995

Relationship between serum tryptophan and tryptophan metabolite levels after tryptophan ingestion in normal subjects and age-related cataract patients.

1. Cataract is the single major cause of blindness worldwide; however, the reasons for the development of this condition remain unknown. It has been suggested that the essential amino acid tryptophan may be implicated in the aetiology but definitive evidence has been lacking. 2. The serum levels of tryptophan and seven of its metabolites have been measured in both cataract patients and control subjects, after administration of tryptophan, in order to determine the typical response profile and to discover whether differences could be found in tryptophan metabolism in the two groups. 3. Tryptophan, kynurenine, kynurenic acid, xanthurenic acid, 3-hydroxyanthranilic acid, 5-hydroxyanthranilic acid, 5-hydroxytryptophan and anthranilic acid were measured by HPLC with dual electrochemical and programmable wavelength fluorescence detection. Fasting cataract patients (n = 42) and control subjects (n = 37) were given an oral dose of L-tryptophan and sera were sampled at 0, 1, 2, 4 and 6 h. 4. Statistically significant differences in the distribution of data between the two groups were observed. The responses of kynurenine and 5-hydroxyanthranilic acid were higher in cataract patients, but those of kynurenic acid and total tryptophan were lower than in control subjects. No statistically significant differences in free tryptophan, anthranilic acid, 3-hydroxyanthranilic acid, xanthurenic acid or 5-hydroxytryptophan levels were noted. 5. We conclude that there is a major subgroup of age-related cataract patients with a dysfunction in the metabolism of tryptophan. This may be related to the onset of cataract. The mechanism remains to be established but may operate via the action of tryptophan metabolites, such as 5-hydroxyanthranilic acid, which become reactive towards protein upon oxidation.

Age Factors↗

PubMed2026

Malaria and cancer: common features and interactions.

Malaria and cancer are major global health burdens, causing high mortality. While often considered distinct, the two conditions share common features, including continuous cell replication within the body, systemic inflammation, immune modulation and evasion, metabolic reprogramming, endothelial dysfunction, and drug efflux mechanisms. Interestingly, whereas malaria parasite infection promotes Burkitt lymphoma, recent studies in animal models indicate that malaria may activate immune mechanisms against various tumors, thereby improving survival rates. The malaria protein VAR2CSA specifically binds to chondroitin sulfate A in the placenta and metastatic cancer cells, which can be exploited for cancer detection and treatment. Studying the common and unique features of malaria and cancer may facilitate the development of treatment strategies for both diseases.

Humans↗

PubMed1994

Serum concentrations of albumin, C-reactive protein, alpha 2-macroglobulin, prealbumin, fibronectin, fibrinogen, transferrin, and retinol binding protein in 55 patients with hepatic glycogen storage diseases.

Hepatic glycogen storage diseases are hereditary metabolic disorders involving the metabolism of glycogen. This study was designed to investigate the serum protein status in such diseases. Fifty-five patients with glycogen storage disease types I, III, VI, and IX, whose ages ranged from 1 month to 27 years, were included in this work. C-reactive protein, fibrinogen, alpha 2-macroglobulin, albumin, transferrin, fibronectin, retinol binding protein, and prealbumin serum concentrations were measured in each patient. In patients affected with type I glycogen storage disease, serum concentrations of alpha 2-macroglobulin, fibrinogen, C-reactive protein, and transferrin were significantly increased. In patients with types III, VI, and IX glycogen storage diseases, the concentration of alpha 2-macroglobulin was the only one that was significantly increased. Thus, even though this study raises more questions than it answers, it seems likely that the hepatic synthesis of some proteins may be increased in patients affected by hepatic glycogen storage diseases. This may indicate some degree of mild hepatic dysfunction in such metabolic disorders. However, further investigations are required to elucidate the discrepancies observed among the different types of diseases.

Adolescent↗

PubMed1996

Serum cholesterol, cholesterol precursors and plant sterols in different inflammatory bowel diseases.

The role of cholestasis and ileal dysfunction on sterol metabolism was studied in 79 patients with inflammatory bowel diseases (IBDs) and in 23 irritable bowel syndrome (IBS) controls by determining serum sterol/cholesterol proportions. The sterols included cholesterol precursors (delta 8-cholestenol, desmosterol and lathosterol), markers of cholesterol synthesis, cholestanol and plant sterols (campesterol and sitosterol), markers of cholesterol absorption and biliary secretion. The IBD patients were subgrouped into distal ulcerative colitis (dUC, n = 21), pancolitis (pUC, n = 29), ileal Crohn's disease (iCD, n = 20) and colonic Crohn's disease (cCD, n = 9). The cholestanol proportions were increased in the 3 colonic IBD groups, up to two times in cCD patients and seven times in a case with clinically overt primary sclerosing cholangitis, but were within the control IBS levels in the patients with iCD. The sitosterol, but not campesterol, proportion was significantly increased only in the pUC group. In the iCD group only the serum precursor sterol proportions, especially those for delta 8-cholestenol and lathosterol, were elevated probably due to ileal dysfunction induced bile acid malabsorption and compensatorily increased cholesterol synthesis. In conclusion, the findings suggest that the increased cholestanol proportion in colonic IBD is determined mainly by impaired biliary elimination of this sterol, while in ileal affision the dominating change in sterol balance is activated cholesterol synthesis. Thus increased serum cholestanol is a novel finding in colonic IBD, apparently indicating the presence of subclinical cholestasis in a marked number (20-50%) of IBD patients.

Adult↗

PubMedDate not supplied

Anoxia and ischemia tolerance in turtle hearts.

It has been known since ancient times that turtle hearts exhibit extraordinary tolerance to anoxia or ischemia. The mechanisms by which they accomplish this remain obscure. The most important adaptation in anoxic turtles is a rapid and dramatic decrease in metabolic rate. Nuclear magnetic resonance measurements indicate that painted turtle (Chrysemys picta) hearts respond to anoxia with a rapid decrease in phosphocreatine (PCr; to 50% of control) after which PCr remains constant for at least 4 h. ATP is defended and does not decrease while intracellular pH (pHi) decreases by 0.2 pH units early in anoxia and is then maintained constant. Softshelled turtles (Trionyx spinifer) have been demonstrated to be far more sensitive than painted turtles to anoxia in vivo. However, isolated hearts from softshelled turtles appear to be as anoxia tolerant as those of Chrysemys. During ischemia there is also little difference in cardic performance, high energy phosphates, or pHi between these two species. A peculiar feature of turtle hearts is an extremely high concentration of phosphodiesters (PDE). The role of cytosolic PDEs remains controversial but they may function as lysophospholipase inhibitors and thereby limit phospholipid turnover (Burt CT and Ribolow H, Comparative Biochemistry and Physiology, 108B: 11-20, 1994). Whether PDEs promote anoxia/ischemia tolerance is unknown but these stresses can result in membrane lipid dysfunction in mammals. Metabolic control, acid-base, and phospholipid homeostasis all play a role in anoxia and ischemia tolerance in turtle hearts. These physiologic processes are interdependent, and how they interact in these animals is unknown, but they are experimentally accessible by modern analytical methods.

Adenosine Triphosphate↗

PubMed2002

Frontal lobe differences in bipolar disorder as determined by proton MR spectroscopy.

OBJECTIVES: Proton magnetic resonance spectroscopy (MRS) provides insight into neurochemical processes. Imaging and postmortem studies have implicated abnormalities of structure and function within the frontal lobe. Patients with bipolar disorder having a manic or mixed episode were hypothesized to demonstrate metabolic abnormalities within the frontal lobe. METHODS: Seventeen patients with bipolar disorder type I (ages 16-35 years, mean 22 +/- 7.3 years) hospitalized for a manic (n = 9) or mixed (n = 8) episode and 21 healthy subjects (ages 16-35 years, mean 21.7 +/- 5.2 years) were evaluated with proton MRS. The gray matter medially and white matter laterally within the frontal lobe were sampled. Metabolite concentrations were calculated for each voxel, corrected for cerebral spinal fluid (CSF) contributions to the voxel, and compared between study populations. RESULTS: Patients demonstrated with multivariate analyses of variance (MANOVA) a significant overall difference in gray matter metabolite concentrations compared with healthy subjects. The largest effect sizes for group differences were found with reductions of N-acetyl aspartate (NAA) and Choline (Cho) concentrations (f = 0.41 and 0.37, respectively). A significant group difference with MANOVA in white matter metabolite concentrations was also observed with the largest effect size at f = 0.44 for elevation of the composite amino acid (AA) concentration. CONCLUSIONS: A reduction of NAA within the gray matter of patients suggests neuronal dysfunction. Altered phospholipid metabolism suggestive of a trend toward decreased volume is implicated with a reduction of Cho concentrations. Within white matter, composite concentrations of AAs were elevated in patients indicating altered neurotransmission.

Adolescent↗

PubMed2001

Physiology and pathophysiology of the serotonergic system and its implications on mental and physical performance. Part I.

Serotonin (5-HT), one of the evolutionary oldest central neurotransmitters, regulates the most extensive modulatory behavioral system in the brain of vertebrates. 5-HT projections are influenced by extrinsic and intrinsic impulses from different cortical brain areas, which reach Raphe nuclei over feedback loops, containing external and internal body information about planning, evaluation, motivation or excitation. Serotonergic neurotransmission adjusts neuromodulation with consecutive adequate stimulation of the neuronal network. This depends on appropriate equilibration of presynaptic 5-HT storage and release but also on 5-HT reuptake from synaptic cleft by 5-HT transporters. The associated pre and postsynaptic 5-HT receptor cooperation, postsynaptic second messenger response and phosphoinositide signaling mediated by postsynaptic 5-HT(2) receptor subpopulation alter signal transduction in which myristolated alanine rich C kinase substrate is prominently involved in regulation of further central 5-HT areas in the brain and corresponding functional neuronal changes. Even though the central function of 5-HT neurotransmission is dominating in the multifold behavioral regulation, peripheral concentration of tryptophan (TRP) adjusted by hepatic and non-hepatic TRP pyrrolase, TRP liberation from albumin especially by adrenergic stimulation of free fatty acids, TRP passage across the blood-brain barrier and TRP hydroxylase activity are also important for appropriate 5-HT neurotransmission as they affect central 5-HT synthesis. The high adaptability of 5-HT neurotransmission is able to compensate neuromodular dysfunctions in the brain by mechanisms which mediate 5-HT biosynthesis, release, reuptake, pre and postsynaptic receptor stimulation with the respective second messenger response and signal transduction to various areas of the brain which are involved in regulation of behavior, mood, memory, learning and attenuation of obsession, depending on the different vigilance states of the subject. Adequate 5-HT system function supports regulation of intercommunicative neuronal transmission in the brain, which optimizes behavioral neuromodulation during and after transient disturbances of neuromodular behavior caused by stress-induced exertions, but also in permanent disorder such as major depression. Serotonergic neurotransmission improves the clinical course due to compensatory 5-HT impulse correction. This hypothetical interpretation of the serotonergic central neuromodular regulation and interaction with the neuronal network is supported by findings both in functional disturbances and persistent impairments in mental disorders. A comparison of the symptomatology in permanent and transient disturbance of brain neuromodulation enhances our basic knowledge on the regulative factors e. g. in endogenous depression and depressive behavioral changes after exhaustive exercise. This consideration exhibits that the interaction between altered central neuromodulation and peripheral metabolic and hormonal dysfunctions is able to differentiate the etiology of the symptoms. It is suggested that the central neuromodular disturbance of stress-induced causes might initiate the manifestation of the impairment. The theoretical background of this hypothesis is discussed in the present review.

Autoreceptors↗

PubMed2001

Chemical pathology in brain white matter of recently detoxified alcoholics: a 1H magnetic resonance spectroscopy investigation of alcohol-associated frontal lobe injury.

BACKGROUND: Investigations have suggested that frontal lobe abnormalities are a prominent feature of the alcoholic brain, indicated by impaired neuropsychological performance on tests of frontal lobe function and by reduced frontal lobe volume in neuroimaging and neuropathological examinations. White matter compartment volume loss may underlie observed brain shrinkage and cognitive deficits associated with the frontal lobes, although the nature of this change has not been well-characterized. METHOD: To investigate the susceptibility of frontal lobe white matter to alcohol-associated metabolic change and to understand the nature of alcohol-related white matter injury, 1H magnetic resonance spectroscopy (MRS) was used to measure concentrations of metabolites in frontal white matter (FWM) and parietal white matter (PWM) of recently detoxified alcoholics (RDA) and nonalcoholic controls (CON). Concentrations of N-acetylaspartate (NAA), choline-containing compounds (Cho), myo-inositol (Ins), and creatine plus phosphocreatine (Cr) were measured in 37 RDA (mean age, 40.4 years; mean length of abstinence, 27.9 days) and 15 CON (mean age, 38.0 years). RESULTS: Analysis of variance (ANOVA) revealed a group by region of interest interaction for concentrations of NAA. Simple effects analysis revealed a significant 14.7% reduction in FWM NAA, while NAA levels in PWM were similar in RDA and CON. In addition, RDA had an 11.8% increase (averaged across both regions of interest) in brain white matter Ins relative to CON. Reductions in FWM NAA were associated with a longer drinking history in the RDA group, but this result was not found when both age and drinking history were used to predict the level of FWM NAA. CONCLUSIONS: Alcohol-associated reductions in FWM NAA may be the result of neuronal loss or dysfunction in the metabolism of NAA. While alcohol-induced oxidative stress may cause global brain impairments in the metabolism and subsequent reduction of NAA, the frontal lobes are particularly rich in excitatory amino acid pathways, and axonal damage or destruction secondary to glutamate-mediated excitotoxicity during alcohol withdrawal may cause frontal lobe-specific reductions in NAA. Elevations in brain white matter Ins may reflect astrocyte proliferation as well as an osmotic response to cell shrinkage.

Adult↗

PubMed1998

Hemodynamic and metabolic responses to repeated hemorrhage and resuscitation with hypertonic saline dextran in conscious swine.

Previous work in our laboratory has demonstrated that HSD is an effective small-volume resuscitation fluid for the treatment of hemorrhagic hypotension, but limitations to its usefulness in severe hemorrhage have not been explored. In the present study, animals (N = 12) were bled from an arterial line at a rate of 1 mL/kg/min until continuously monitored aortic blood flow was reduced to one-half its baseline value, and then they were immediately resuscitated with 7.5% NaCl/6% dextran 70 (hypertonic saline dextran, 4 mL/kg) administered intravenously over 3 min. After recording the maximum improvement in blood pressure, blood samples were obtained and the hemorrhage-resuscitation sequence was repeated until no further measurable increase in cardiac index or blood pressure could be elicited by resuscitation. In the majority of the animals, cardiac index and right and left ventricular stroke work could be improved at least through two bleedings and resuscitation. These improvements sufficed to increase oxygen delivery and consumption, despite the decreases in hematocrit induced by bleeding, transcapillary refill, and asanguinous fluid administration. Under these severe hemorrhage conditions, the acid-base imbalance was not improved by hypertonic saline dextran, and the rate of increase in acidosis was not affected by its administration. We observed a progressive decrease in base excess from +1.35+/-3.19 (mean +/- standard error) to -12.9+/-2.1 mEq/L even when resuscitation improved oxygen consumption significantly by 95+/-20%. In animals that survived as many as three bleedings and resuscitation, the depletion of buffering capacity of the blood was most predominant, and bicarbonate reached a nadir of 7.62 mEq/L with a base excess of -22.4 mEq/L. It is evident that restoration of perfusion in shock treats only a portion of the physiologic dysfunction, leaving major metabolic derangements uncorrected.

Acid-Base Equilibrium↗

PubMed2005

Effect of dietary polyunsaturated fatty acids on age-related changes in cardiac mitochondrial membranes.

Remodeling of myocardial cell membranes is a major feature of advanced age. Mitochondrial function, crucial to sustaining energy production and management of myocardial metabolism, is impacted by age-dependent remodeling and ultimately exhibits a diminished threshold for excess Ca(2+) buffering during events that stimulate increased myocardial Ca(2+), such as augmented cardiac work, oxidative stress or post-ischemic reflow. Relative Ca(2+) intolerance, augmented superoxide formation and reduced efficiency in the management of reactive oxygen species, are important mitochondrial factors (of many) that are apparent in senescence and predispose the myocardium to be more vulnerable to ischemic injury. In addition to cell death, surviving myocytes increase in size and exhibit altered gene expression of key effector proteins, including those that sustain Ca(2+) homeostasis. Age-associated mitochondrial membrane changes include increases in membrane rigidity, cholesterol, phosphatidylcholine, omega-6 polyunsaturated fatty acids (PUFA), 4-hydroxy-2-nonenal, and decreases in omega-3 PUFA and cardiolipin. These effects have been shown in animal studies to be exaggerated by diet rich in long chain omega-6 PUFA (i.e., arachidonic acid), and have profound consequences on the efficacy of membrane proteins involved with ion homeostasis, signal transduction, redox reactions and oxidative phosphorylation. However, some of the age-related detrimental adaptations may be beneficially modified by dietary strategy. Diet rich in omega-3 PUFA reverses the age-associated membrane omega-3:omega-6 PUFA imbalance, and dysfunctional Ca(2+) metabolism, facilitating increased efficiency of mitochondrial energy production and improved tolerance of ischemia and reperfusion.

Aging↗

PubMed1990

[Experimental studies on the changes of mitochondrial membrane phospholipids during cerebral ischemia and recirculation].

Changes of brain mitochondrial phospholipids during cerebral ischemia and recirculation were experimentally studied in a rat 4-vessel occlusion model, to explore the relation between changes of mitochondrial phospholipids and dysfunction of mitochondria. Respiratory functions, activities of respiratory enzymes (cytochrome c oxidase, F0F1-ATPase) were analyzed after 30 and 60 minutes of ischemia, and after 30 minutes of recirculation following each ischemic period. Activities of respiratory functions and respiratory enzymes decreased progressively during ischemia, which recovered completely after recirculation following 30 minutes of ischemia, while only partial recovery was observed after recirculation following 60 minutes of ischemia. In phospholipid analyses, contents of phospholipid classes tended to decrease time-dependently during ischemia, and compositions of polyunsaturated fatty acids (PUFA) such as arachidonic acid (20:4) and docosahexaenoic acid (22:6) were decreased preferentially. In recirculation, phosphatidylcholine (PC), phosphatidylethanolamine (PE), and cardiolipin (CL) showed recovery of contents of phospholipids and compositions of PUFA after recirculation following 30 minutes of ischemia, while further decrease of contents of phospholipids and compositions of PUFA were observed after recirculation following 60 minutes of ischemia, especially in CL. On the other hand, progressive degradation of phospholipids occurred after recirculation following both 30 and 60 minutes of ischemia in phosphatidylserine and phosphatidylinositol. Changes of major phospholipid classes such as PC, PE, and CL correlated with the changes of mitochondrial respiratory functions and activities of respiratory enzymes. In conclusion, changes of mitochondrial membrane phospholipids appear to affect the integrity of cellular energy metabolism via mitochondrial dysfunction during cerebral ischemia and recirculation.

Animals↗

PubMed1999

Maternal second trimester serum tumor necrosis factor-alpha-soluble receptor p55 (sTNFp55) and subsequent risk of preeclampsia.

Preeclampsia is characterized by diffuse vascular endothelial dysfunction. Tumor necrosis factor-alpha (TNF-alpha), which plays a key role in the cytokine network responsible for immunoregulation, is also known to contribute to endothelial dysfunction and other metabolic disturbances noted in preeclampsia. Results from cross-sectional studies and one longitudinal study indicate that TNF-alpha (or its soluble receptor, sTNFp55) is increased in the peripheral circulation and amniotic fluid of women with preeclampsia as compared with normotensive women. Between December 1993 and August 1994, prediagnostic sTNFp55 concentrations (a marker of excessive TNF-alpha release) were measured in 35 women with preeclampsia and 222 normotensive women to determine whether elevations precede the clinical manifestation of the disorder. Logistic regression procedures were used to calculate maximum likelihood estimates of odds ratios and 95% confidence intervals. Mean second trimester (15-22 weeks' gestation) serum sTNFp55 concentrations, measured by enzyme-linked immunosorbent assay, were 14.4% higher in preeclamptic women than in normotensive controls (716.6 pg/ml (standard deviation 193.6) vs. 626.4 pg/ml (standard deviation 158.0); p = 0.003). The relative risk of preeclampsia increased across successively higher quintiles of sTNFp55 (odds ratios were 1.0, 1.3, 2.1, and 3.7, with the lowest quintile used as the referent; p for trend = 0.007). After adjustment for maternal age, adiposity, and parity, the relative risk between extreme quintiles was 3.3 (95% confidence interval 0.8-13.4). These findings indicate that the level of TNF-alpha in maternal circulation is increased prior to the clinical manifestation of the disorder, and they are consistent with the hypothesized role of cytokines in mediating endothelial dysfunction and the pathogenesis of preeclampsia. Further work is needed to identify modifiable risk factors for the excessive synthesis and release of TNF-alpha in pregnancy, and to assess whether lowering of TNF-alpha concentrations in pregnancy alters the incidence and severity of preeclampsia.

Adolescent↗

PubMed2025

Spike protein-induced VSIR-ISX signaling disrupts metabolic homeostasis and promotes COVID-19-related immune dysfunction.

COVID-19 has caused millions of deaths worldwide since 2019. Vaccination has reduced both transmission and disease severity. However, emerging viral variants have weakened vaccine effectiveness, highlighting the need for new antiviral therapies. This study examines how the SARS-CoV-2-Spike protein (SARS-2-S) induces the VSIR-ISX signaling pathway, leading to metabolic disturbances that may worsen disease progression. Using RNA sequencing, we found that SARS-2-S expression in pulmonary cells activates genes involved in tryptophan and arachidonic acid (AA) metabolism, altering bioactive mediators like kynurenine and prostanoids, which are crucial for inflammation and immune responses. Mechanistically, the ACE2-MYD88 pathway, activated by SARS-2-S, enhances the VSIR-ISX axis through NF-κB signaling, driving these metabolic disruptions. Chromatin immunoprecipitation and genome sequencing revealed that ISX, activated via VSIR-MAPK signaling, upregulates enzymes involved in AA metabolism by binding directly to their gene promoters. Notably, disrupting the VSIR-ISX axis using shRNA interference or NF-κB inhibitors effectively mitigated these metabolic disturbances. Our findings suggest that the VSIR-ISX pathway could be a promising therapeutic target for treating COVID-19 by addressing virus-induced metabolic disruptions.

Humans↗

PubMed2006

Testosterone replacement therapy for treatment refractory cluster headache.

OBJECTIVES: To describe the clinical characteristics and laboratory findings of cluster headache patients whose headaches responded to testosterone replacement therapy. BACKGROUND: Current evidence points to hypothalamic dysfunction, with increased metabolic hyperactivity in the region of the suprachiasmatic nucleus, as being important in the genesis of cluster headaches. This is clinically borne out in the circadian and diurnal behavior of these headaches. For years it has been recognized that male cluster headache patients appear overmasculinized. Recent neuroendocrine and sleep studies now point to an association between gonadotropin and corticotropin levels and hypothalamically entrained pineal secretion of melatonin. RESULTS: Seven male and 2 female patients, seen between July 2004 and February 2005, and between the ages of 32 and 56, are reported with histories of treatment resistant cluster headaches accompanied by borderline low or low serum testosterone levels. The patients failed to respond to individually tailored medical regimens, including melatonin doses of 12 mg a day or higher, high flow oxygen, maximally tolerated verapamil, antiepileptic agents, and parenteral serotonin agonists. Seven of the 9 patients met 2004 International Classification for the Diagnosis of Headache criteria for chronic cluster headaches; the other 2 patients had episodic cluster headaches of several months duration. After neurological and physical examination all patients had laboratory investigations including fasting lipid panel, PSA (where indicated), LH, FSH, and testosterone levels (both free and total). All 9 patients demonstrated either abnormally low or low, normal testosterone levels. After supplementation with either pure testosterone in 5 of 7 male patients or combination testosterone/estrogen therapy in both female patients, the patients achieved cluster headache freedom for the first 24 hours. Four male chronic cluster patients, all with abnormally low testosterone levels, achieved remission. CONCLUSIONS: Abnormal testosterone levels in patients with episodic or chronic cluster headaches refractory to maximal medical management may predict a therapeutic response to testosterone replacement therapy. In the described cases, diurnal variation of attacks, a seasonal cluster pattern, and previous, transient responsiveness to melatonin therapy pointed to the hypothalamus as the site of neurological dysfunction. Prospective studies pairing hormone levels and polysomnographic data are needed.

Adult↗

PubMed1997

The protective effects of L-arginine after liver ischaemia/reperfusion injury in a pig model.

Hepatic ischaemia/reperfusion is characterized by circulatory and metabolic derangement, liver dysfunction, and tissue damage. To evaluate the role of L-arginine, a substrate of nitric oxide, in ischaemia/reperfusion injury, total liver ischaemia was induced for 120 min in 22 Landrace x Large White female pigs, which were randomly assigned to a treatment group (10 animals) or a control group (12 animals). An L-arginine bolus (540 mg/kg i.v.) was administered to the treatment group 1 h before clamping the hepatic hilum, at clamping, at reperfusion, and at 1 and 2 h after reperfusion. The control animals received normal saline and an i.v. infusion. Liver function tests and analysis of serum, erythrocyte, and tissue malondialdehyde contents were performed at commencement of laparotomy, before reperfusion, and at 30 min and 7 days after reperfusion. Liver biopsies were taken at laparotomy, at 30 min, and at 7 days after reperfusion for histological and ultrastructural examination. Assessment of apoptosis included in situ end-labelling analysis and DNA gel electrophoresis. Survival at 7 days was better in the treated animals than in the controls (9/10 vs. 7/12). Tissue malondialdehyde content, aspartate aminotransferase, and lactate dehydrogenase levels were lower in the treatment group, in which morphological changes were significantly less evident than in the controls 30 min after reperfusion. At 7 days, differences between the groups with respect to cell integrity were apparent only on ultrastructural analysis. Glycogen content, 7 days after reperfusion, was higher in the treatment group than in the controls: 70.25 per cent vs. 21.66 per cent positive hepatocytes (score 3 vs. score 1). Multiparametric analysis showed fewer apoptotic cells in the treatment group at all times. Our data show that the administration of L-arginine reduces damage to liver tissue after ischaemia/reperfusion injury in a pig model. This may be explained not only by the known vasodilator, anti-aggregation, and superoxide inactivation effects of increased nitric oxide release, but possibly also by some other action of L-arginine, such as its influence on cellular metabolism.

Animals↗

PubMed2006

CVD risk factors and ethnicity--a homogeneous relationship?

Current understanding of cardiovascular disease risk (CVD) is derived largely from studies of Caucasians of European origin. However, people of certain ethnic groups experience a disproportionately greater burden of CVD including coronary heart disease (CHD) and stroke. Adoption of a Westernised lifestyle has different effects on metabolic and vascular dysfunction across populations, e.g. South Asians have a higher prevalence of coronary heart disease (CHD) and cardiovascular mortality compared with Europeans. African-Americans demonstrate higher rates of CHD and stroke while African/Caribbeans in the UK have lower CHD rates and higher stroke rates than British Europeans. Other non-European groups such as the Chinese and Japanese exhibit consistently high rates of stroke but not CHD, while Mexican Americans have a higher prevalence of both stroke and CHD, and North American native Indians also have high rates of CHD. While conventional cardiovascular risk factors such as smoking, blood pressure and total cholesterol predict risk within these ethnic groups, they do not fully account for the differences in risk between ethnic groups, suggesting that alternative explanations might exist. Ethnic groups show differences in levels of visceral adiposity, insulin resistance, and novel risk markers such as C-reactive protein (CRP), adiponectin and plasma homocysteine. The marked differences across racial and ethnic groups in disease risk are likely due in part to each of genetic, host susceptibility and environmental factors, and can provide valuable aetiological clues to differences in patterns of disease presentation, therapeutic needs and response to treatment. Ongoing studies should increase understanding of ethnicity as a potential independent risk factor, thus enabling better identification of treatment targets and selection of therapy in specific populations.

Biomarkers↗

PubMed1993

Skeletal muscle bioenergetics in myotonic dystrophy.

Skeletal muscle function of 15 patients with myotonic dystrophy (dystrophia myotonica, DM) was investigated using 31P magnetic resonance spectroscopy to evaluate bioenergetics and intracellular pH at rest and during exercise and recovery. Results from DM patients, normal controls and mitochondrial myopathy patients were compared in order to assess the possible contribution of abnormal mitochondrial metabolism to muscle dysfunction in DM. In resting DM muscle, intracellular pH (pHi) was normal, but there were significant elevations in the concentration ratios of Pi/ATP, phosphomonoesters/ATP and phosphodiesters/ATP. In patients with the most severe exercise intolerance the phosphocreatine/ATP ratio was also reduced. Resting muscle of 11 mitochondrial myopathy patients showed similar changes to those of the most exercise-intolerant DM patients. In exercising DM muscle, energy stores were rapidly depleted as in mitochondrial myopathy. Muscle acidified in all subjects, but in DM the decrease in pHi was less than in normal muscle. Recovery half-times for phosphocreatine, Pi and ADP were normal in DM but slow in mitochondrial myopathy. The initial rate of phosphocreatine repletion after exercise was rapid in DM, consistent with high [ADP], but slow in mitochondrial myopathy in spite of elevated [ADP]. Because recovery is an oxidative process, we conclude that there was no decrease in the oxidative capacity of the muscles in this group of DM patients. In the subjects in whom it could be measured, the rate of recovery of intracellular pH was greater in the 3 DM patients (0.14, 0.15 and 0.16 U/min) than in the 7 normal controls (0.08-0.12 U/min, mean 0.10). The results do not rule out a minor abnormality in glycogenolysis, but they suggest that the failure to acidify normally during exercise is probably due to rapid proton efflux.

Adenosine Diphosphate↗

PubMed1996

Effect of acetaminophen administration on hepatic glutathione compartmentation and mitochondrial energy metabolism in the rat.

Changes in cell energy metabolism and mitochondrial dysfunction have been observed after acetaminophen administration. Because consumption of hepatic glutathione is closely related to acetaminophen toxicity, we investigated the kinetics of: 1. glutathione depletion in liver mitochondria and cytosol; 2. State 3 and 4 respiratory rates of succinate-supplemented mitochondria; 3. rate of ATP synthesis; 4. oligomycin-sensitive ATP hydrolase activity and passive proton conductivity of inside-out vesicles of the inner mitochondrial membrane; and 5. changes in hepatic and mitochondrial malondialdehyde in the rat after in vivo acetaminophen administration. Two hours after acetaminophen injection, hepatic glutathione decreased and malondialdehyde increased. In the same interval, an increase in both State 3 and 4 respiratory rates of succinate-supplemented mitochondria was observed. This was accompanied by a decrease in the rate of ATP synthesis and the P/O ratio and by an increase in the passive proton permeability of the inner mitochondrial membrane, which was insensitive to oligomycin. No significant change in oligomycin-sensitive ATP hydrolase activity was observed. Four hours after APAP injection, the respiratory rates, as well as the proton conductivity, decreased, the rate of ATP synthesis was restored, and the mitochondrial glutathione started to increase; the cytosolic levels of glutathione were still low and the cytosolic and mitochondrial levels of malondialdehyde remained high for 2 more hr. The concentrations of these indices were completely restored 24 hr postdosing. Our findings suggest that acetaminophen administration selectively depletes (within 2 hr) mitochondrial glutathione, and produces local toxicity by altering membrane permeability and decreasing the efficiency of oxidative phosphorylation. This renders mitochondria more susceptible to oxidative damage, especially during increased free radical production, as in the case of enhanced mitochondrial respiration in State 4. The concomitant restoration of mitochondrial respiration, oxidative phosphorylation, membrane permeability, and glutathione levels is consistent with the importance of the mitochondrial glutathione pool for the protection of the mitochondrial membrane against oxidative damage.

Acetaminophen↗