Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that the polychlorinated biphenyl mixture, Aroclor 1254 (ARO), -induced wasting in male rats is associated with increased permeability of hepatic mitochondria. This was correlated with hyperuremia and stimulated urea synthesis, hypoglycemia and suppressed glucogenesis after an ammonium acetate injection, and decreased retention of assimilated nitrogen and food intake. For ARO-toxic rats (100 mg/kg, ip, for 1, 2, and 4 days) versus Tween 80-treated, ad libitum-fed controls, mitochondrial carbamoyl phosphate (CP) formation (the initial step in urea synthesis from NH4+) was progressively stimulated for the duration of treatment from NH4+ and ATP but not from NH4+ and ADP. ARO maximal stimulation of CP formation also correlated with significant loss in body weight. Mitochondrial ornithine transcarbamoylase synthesis of citrulline from ornithine and carbamoyl phosphate was also stimulated. In comparison to fasted rats (24 hr), mitochondrial CP synthesis from NH4+ was enhanced with ADP but not with ATP. This ARO uncoupling of mitochondrial NH4+ metabolism and stimulation of CP formation with exogenous ATP and citrulline synthesis may have resulted from increased availability of substrates and cofactors in the matrix space, leakage of enzymes from the matrix, or a combination of these effects. These results are consistent with an increased inner membrane permeability and fragility during isolation and assays. In agreement with our previous studies, the data show that ARO exposure poises hepatic mitochondria toward the synthesis of urea intermediates.
 ...
PMID:Aroclor 1254 treatment and fasting influences on rat liver mitochondrial carbamoyl phosphate synthesis with ADP and ATP. 314 1

Chronic sepsis is always associated with profound wasting leading to increased release of amino acids from skeletal muscle. Net protein catabolism may be due to decreased rate of synthesis, increased rate of degradation, or both. To determine whether protein synthesis is altered in chronic sepsis, the rate of protein synthesis in vivo was estimated by measuring the incorporation of [3H]-phenylalanine in skeletal muscle protein in a chronic (5-day) septic rat model induced by creation of a stable intra-abdominal abscess using an E. coli + B. fragilis-infected sterile fecal-agar pellet as foreign body nidus. Septic rats failed to gain weight at rates similar to control animals, therefore control animals were weight matched to the septic animals. The skeletal muscle protein content in septic animals was significantly reduced relative to control animals (0.18 +/- 0.01 vs. 0.21 +/- 0.01 mg protein/gm wet wt; p less than 0.02). The rate of incorporation of [3H]-phenylalanine into skeletal muscle protein from control animals was 39 +/- 4 nmole/gm wet wt/hr or a fractional synthetic rate of 5.2 +/- 0.5%/day. In contrast to control animals, the fractional synthetic rate in septic animals (2.6 +/- 0.2%/day) was reduced by 50% compared to control animals (p less than 0.005). The decreased rate of protein synthesis in sepsis was not due to an energy deficit, as high-energy phosphates and ATP/ADP ratio were not altered. This decrease in protein synthesis occurred even though septic animals consumed as much food as control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Inhibition of skeletal muscle protein synthesis in septic intra-abdominal abscess. 339 97

Conditions to induce and parameters to evaluate sublethal oxidative stress of cultured human fibroblasts have been investigated in the attempt to identify markers for a more accurate quantification of cell injury. Sublethal oxidative stress was obtained by treating fibroblasts with 0.5 mM H2O2 in DMEM plus 5% FCS for times not exceeding 60 min. Under these conditions cells remained viable throughout long-term incubation, showing no appreciable release of cytosolic enzymes into the medium. On the contrary, exposures of fibroblasts to 0.5 mM H2O2 for times > 60 min induced a lethal cell injury which was fully expressed 2 days later by massive monolayer wasting and leakage of cytosolic components. Early metabolic effects of sublethal stress consisted of a rapid and significant fall of both ATP and NAD+ pools. Concomitantly, there was a moderate increase (about threefold) in both ADP-ribosyl transferase activity and free [Ca2+]i, while the specific activity of glyceraldehyde-3-phosphate dehydrogenase was partially decreased upon treatment. Oxidative injury also caused delayed effects consisting of a large depression of both protein and DNA synthesis. However, while the former was partially restored within 10 days of incubation, the latter remained severely impaired, as encountered in a growth-arrested population. Microfilaments of H2O2-treated cells appeared to be morphologically altered due to partial fragmentation of cytoskeleton actin which, however, was still maintained in the polymerized form as F-actin. Moreover, sublethally injured fibroblasts exhibited a reduced adhesiveness to plastic once they were detached and reseeded into new dishes. Relative adhesion efficiencies (number of adherent cells at 16 h as a percentage of seeded cells) were found to correlate inversely with times of exposure to H2O2. This finding allowed the identification of a biological parameter which showed itself to be very sensitive to oxidative stress and was also useful for developing an assay to grade sublethal injury to fibroblasts.
 ...
PMID:Induction, effects, and quantification of sublethal oxidative stress by hydrogen peroxide on cultured human fibroblasts. 784 83

The heart is known for its ability to produce energy from fatty acids (FA) because of its important beta-oxidation equipment, but it can also derive energy from several other substrates including glucose, pyruvate, and lactate. The cardiac ATP store is limited and can assure only a few seconds of beating. For this reason the cardiac muscle can adapt quickly to the energy demand and may shift from a 100% FA-derived energy production (after a lipid-rich food intake) or any balanced situation (e.g., diabetes, fasting, exercise). These situations are not similar for the heart in terms of oxygen requirement because ATP production from glucose is less oxygen-consuming than from FA. The regulation pathways for these shifts, which occur in physiologic as well as pathologic conditions (ischemia-reperfusion), are not yet known, although both insulin and pyruvate dehydrogenase activation are clearly involved. It becomes of strategic importance to clarify the pathways that control these shifts to influence the oxygen requirement of the heart. Excess FA oxidation is closely related to myocardial contraction disorders characterized by increased oxygen consumption for cardiac work. Such an increased oxygen cost of cardiac contraction was observed in stunned myocardium when the contribution of FA oxidation to oxygen consumption was increased. In rats, an increase in n-3 polyunsaturated FA in heart phospholipids achieved by a fish-oil diet improved the recovery of pump activity during postischemic reperfusion. This was associated with a moderation of the ischemia-induced decrease in mitochondrial palmitoylcarnitine oxidation. In isolated mitochondria at calcium concentrations close to that reported in ischemic cardiomyocytes, a futile cycle of oxygen wastage was reported, associated with energy wasting (constant AMP production). This occurs with palmitoylcarnitine as substrate but not with pyruvate or citrate. The energy wasting can be abolished by CoA-SH and other compounds, but not the oxygen wasting. Again, the calcium-induced decrease in mitochondrial ADP/O ratio was reduced by increasing the n-3 polyunsaturated FA in the mitochondrial phospholipids. These data suggest that in addition to the amount of circulating lipids, the quality of FA intake may contribute to heart energy regulation through the phospholipid composition. On the other hand, other intervention strategies can be considered. Several studies have focused on palmitoylcarnitine transferase I to achieve a reduction in beta-oxidation. In a different context, trimetazidine was suggested to exert its anti-ischemic effect on the heart by interfering with the metabolic shift, either at the pyruvate dehydrogenase level or by reducing the beta-oxidation. Further studies will be required to elucidate the complex system of heart energy regulation and the mechanism of action of potentially efficient molecules.
 ...
PMID:Fatty acid oxidation in the heart. 889 66

Stimulation of brown adipocytes by their sympathetic innervation plays a major role in body energy homeostasis by regulating the energy-wasting activity of the tissue. The norepinephrine released by sympathetic activity acts on adrenergic receptors to activate a variety of metabolic and membrane responses. Since sympathetic stimulation may also release vesicular ATP, we tested brown fat cells for ATP responses. We find that micromolar concentrations of extracellular ATP initiates profound changes in the membrane trafficking of brown adipocytes. ATP elicited substantial increases in total cell membrane capacitance, averaging approximately 30% over basal levels and occurring on a time scale of seconds to minutes. The membrane capacitance increase showed an agonist sensitivity of 2-methylthio-ATP > or = ATP > ADP > > adenosine, consistent with mediation by a P2r type purinergic receptor. Membrane capacitance increases were not seen when cytosolic calcium was increased by adrenergic stimulation, and capacitance responses to ATP were similar in the presence and absence of extracellular calcium. These results indicate that increases in cytosolic calcium alone do not mediate the membrane response to ATP. Photometric assessment of surface-accessible membrane using the dye FM1-43 showed that ATP caused an approximate doubling of the amount of membrane actively trafficking with the cell surface. The discrepancy in the magnitudes of the capacitance and fluorescence changes suggests that ATP both activates exocytosis and alters other aspects of membrane handling. These findings suggest that secretion, mobilization of membrane transporters, and/or surface membrane expression of receptors may be regulated in brown adipocytes by P2r purinergic receptor activity.
 ...
PMID:Purinergic receptor stimulation increases membrane trafficking in brown adipocytes. 892 65

Sympathetic stimulation of brown adipocytes plays a major role in body energy homeostasis by activating energy-wasting pathways. Sympathetic neuronal input initiates a variety of metabolic, developmental, and membrane responses in brown fat cells. Many of these actions are mediated by adrenergic pathways mobilized by released norepinephrine. However, since sympathetic stimulation may also release vesicular ATP, we tested brown fat cells for ATP responses. Micromolar concentrations of extracellular ATP had a number of effects on brown adipocytes. We have shown previously that ATP elicits substantial (average of approximately 30%) increases in cell membrane capacitance (P. A. Pappone and S. C. Lee, J. Gen. Physiol. 108: 393-404, 1996). Here, we show that cytosolic calcium levels were increased by ATP, both through release from intracellular stores and through influx, as assessed by fura 2 imaging. In addition, ATP indirectly activated a nonselective cation conductance that was independent of cytosolic calcium levels in patch voltage-clamped brown fat cells. Similar calcium, conductance, and capacitance responses could be activated by 2-methylthio-ATP and ADP, consistent with mediation by a P2 type purinergic receptor. Calorimetric measurements from cell suspensions showed that ATP increased basal heat production of isolated brown fat cells by approximately 40% but had no effect on the greater than fivefold increase in heat production seen with maximal adrenergic stimulation. These myriad responses to extracellular ATP suggest that P2 receptor-mediated signaling is important in brown adipocyte physiology and that sympathetic stimulation may normally activate purinergic as well as adrenergic pathways in brown fat.
 ...
PMID:Effects of P2 purinergic receptor stimulation in brown adipocytes. 927 66

This study was carried out in order to determine if the efficiency of amiodarone, a class III antiarrhythmic agent, is associated with changes in mitochondrial oxidative phosphorylation. A population of 30 rats were treated with amiodarone (100 mg/kg/day) for 5 days. A second population receiving only vehicle was used as control. The hearts were perfused according to the working mode. After 15 min of normoxic perfusion, the left main coronary artery was ligated and the ligation was maintained for 20 min. The ligation was removed and reperfusion continued for a further 30 min. The electrocardiogram was monitored continuously. At the end of perfusion, the ischemic and non ischemic areas were visually separated and mitochondria were harvested from each area. Their oxidative and energy metabolism were assessed with palmitoylcarnitine as substrate in 2 respiration media differing in their free calcium concentration (0 or 0.34 microm). In normoxic conditions, amiodarone treatment increased the cardiac metabolic efficiency (mechanical work to oxygen consumption ratio). The local ischemia decreased the aortic and coronary flows without modifying the cardiac metabolic efficiency. Amiodarone treatment maintained the aortic flow at a significantly higher value; the duration of severe arrhythmias was significantly decreased by the drug. The reperfusion of the ischemic area allowed the partial recovery of fluid dynamics. The coronary flow was restored to 89% of the pre ischemic value. Conversely, the aortic flow never exceeded that measured at the end of ischemia, partly due to the important development of severe arrhythmias. The recovery of aortic flow and metabolic efficiency during reperfusion was improved by amiodarone treatment; ventricular tachycardia and fibrillation duration were reduced. In the mitochondria issued from the normoxic area, the energy metabolism was not altered by the amiodarone treatment, but the presence of calcium in the respiration medium modified the oxidative phosphorylation. The divalent cation slightly decreased the state III respiration rate and increased noticeably the state IV respiration rate. This was associated with an important mitochondrial AMP production and maintenance of ADP in the respiration medium. This energy wasting was reported to decrease the mitochondrial metabolic efficiency. After an ischemia-reperfusion sequence, mitochondrial oxidation phosphorylation was reduced and amiodarone treatment amplified this decrease. This was presumably due to an increased mitochondrial calcium accumulation. Thus, the beneficial properties of amiodarone during reperfusion are supposed to be due to a protection against the deleterious effect of excess matrix calcium on mitochondrial energy metabolism.
 ...
PMID:Effects of amiodarone on cardiac function and mitochondrial oxidative phosphorylation during ischemia and reperfusion. 1039 Nov 52

The purpose of this study was to modify the amount of 22:4 n-6, 22:5 n-6 and 20:5 n-3 in cardiac phospholipids and to evaluate the influence of these changes on the functioning of working rat hearts and mitochondrial energy metabolism under normoxic conditions and during postischemic reperfusion. The animals were fed one of these four diets: (i) 10% sunflower seed oil (SSO); (ii) 10% SSO + 1% cholesterol; (iii) 5% fish oil (FO, EPAX 3000TG, Pronova) + 5% SSO; (iv) 5% FO + 5% SSO + 1% cholesterol. Feeding n-3 PUFA decreased n-6 PUFA and increased n-3 PUFA in plasma lipids. In the phospholipids of cardiac mitochondria, this dietary modification also induced a decrease in the n-6/n-3 PUFA ratio. Cholesterol feeding induced marked hepatic steatosis (HS) characterized by the whitish appearance of the liver. It also brought about marked changes in the fatty acid composition of plasma and mitochondrial phospholipids. These changes, characterized by the impairment of deltaS- and delta6-desaturases, were more obvious in the SSO-fed rats, probably because of the presence of the precursor of the n-6 family (linoleate) in the diet whereas the FO diet contained large amounts of eicosapentaenoic and docosahexaenoic acids. In the mitochondrial phospholipids of SSO-fed rats, the (22:4 n-6 + 22:5 n-6) to 18:2 n-6 ratio was decreased by HS, without modification of the proportion of 20:4 n-6. In the mitochondrial phospholipids of FO-fed rats, the amount of 20:5 n-3 tended to be higher (+56%). Cardiac functioning was modulated by the diets. Myocardial coronary flow was enhanced by HS in the SSO-fed rats, whereas it was decreased in the FO-fed animals. The rate constant k012 representing the activity of the adenylate kinase varied in the opposite direction, suggesting that decreased ADP concentrations could cause oxygen wasting through the opening of the permeability transition pore. The recovery of the pump function tended to be increased by n-3 PUFA feeding (+22%) and HS (+45%). However, the release of ascorbyl free radical during reperfusion was not significantly modified by the diets. Conversely, energy production was increased by ischemia/reperfusion in the SSO group, whereas it was not modified in the FO group. This supports greater ischemia/reperfusion-induced calcium accumulation in the SSO groups than in the FO groups. HS did not modify the mitochondrial energy metabolism during ischemia/reperfusion. Taken together, these data suggest that HS- and n-3 PUFA-induced decrease in 22:4 and 22:5 n-6 and increase in 20:5 n-3 favor the recovery of mechanical activity during post-ischemic reperfusion.
 ...
PMID:Effects of dietary polyunsaturated fatty acids and hepatic steatosis on the functioning of isolated working rat heart under normoxic conditions and during post-ischemic reperfusion. 1169 87

Silver syndrome (SS) is a complicated form of hereditary spastic paraplegia associated with distal wasting of the small muscles of the hands. We have previously described a large kindred with SS and mapped a genetic locus (SPG17) to chromosome 11q12-q14. In the current study we analyse the clinical phenotype and perform linkage analysis in three new SS families. In addition we analyse candidate genes mapping to the SS locus (SPG17). Clinical assessments were performed on 25 (15 affected) individuals from each family in which SS segregates with variable clinical expression. Neurophysiological studies, performed in the index case of two families, suggested anterior horn cell or nerve root involvement. Linkage analysis using microsatellite markers mapping to the SPG17 locus was performed and only one of the three families had a microsatellite segregation pattern compatible with linkage. Candidate genes mapping to the SS critical region were analysed in this and one other SPG17-linked family. Mutation analysis of genes encoding calpain 1 ( CAPN1), copper chaperone for superoxide dismutase ( CCS), ADP ribosylation factor-like 2 ( ARL2), LOC120664, a putative homologue of atlastin ( ATLSTL-1) and sorting nexin 15 ( SNX15) failed to identify any disease-specific mutations. SS therefore exhibits both clinical and genetic heterogeneity and the SPG17 locus may account for a significant proportion of SS mutations in the UK.
 ...
PMID:A clinical, genetic and candidate gene study of Silver syndrome, a complicated form of hereditary spastic paraplegia. 1537 47

Numerous experimental and clinical studies have shown that skeletal muscle apoptotis may increase in wasting conditions and suggest that apoptosis might contribute to the loss of lean body mass. Data in cancer patients are still lacking. The present study aimed at verifying whether apoptosis was enhanced in the skeletal muscle of 16 patients with gastric cancer with respect to controls. A biopsy specimen was obtained from the rectus abdominis muscle. The occurrence of apoptosis in muscle biopsies was determined morphologically by the fluorescent transferase-mediated dUTP nick end labeling assay and by immunohistochemistry for caspase-3 and caspase-1. Mean weight loss was 6+/-2% in cancer patients and 0.5+/-0.1% in controls (p<0.0001). Serum albumin levels (g/dL) were 3.7+/-0.3 in cancer patients and 4.1+/-0.2 in controls (p<0.05). The percentage of apoptotic myonuclei was similar in cancer patients and in controls (1.5+/-0.3 versus 1.4+/-0.2, respectively; p=ns), in gastric cancer patients with mild (1.6+/-0.4) or moderate-severe weight loss (1.4+/-0.5) (p=ns), and in the different stages of disease (stages I-II: 1.5+/-0.7; stage III: 1.3+/-0.4; stage IV: 1.6+/-0.3; p=ns). By immunohistochemistry, caspase-1 and caspase-3 positive fibers were absent in controls and in neoplastic patients. Poly-ADP-ribosyl polymerase, a typical caspase-3 substrate whose processing is indicative of caspase-3 activation, was not cleaved in muscle biopsies of cancer patients. These data suggest that skeletal muscle apoptosis is not increased in neoplastic patients with mild-moderate weight loss and argue against the hypotheses that caspase-3 activation might be an essential step of myofibrillar proteolysis in cancer-related muscle wasting.
 ...
PMID:Skeletal muscle apoptosis is not increased in gastric cancer patients with mild-moderate weight loss. 1669 91


1 2 Next >>