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

The objectives of this study were to investigate whether oral supplementation of L-2-oxothiazolidine-4-carboxylate (OTC) is effective for increasing tissue glutathione (GSH) concentrations in rats fed a diet very low (0.5%) in protein-a model of wasting malnutrition-and to determine the efficacy of OTC for protection against pulmonary oxygen toxicity. Weanling rats, fed a 0.5 or 15% protein diet for 2 wk, were given an oral supplement of OTC, and tissue GSH concentrations were measured over a 24 h period. OTC supplementation to rats fed 0.5% protein significantly increased GSH concentrations in liver and lung, but not in kidney and blood, when compared with the 0.5% protein unsupplemented group. The liver GSH concentration in the 0.5% protein OTC-supplemented group was higher than the 15% control group. Daily supplementation of OTC protected rats from pulmonary oxygen toxicity during 4 days of 85% oxygen exposure as determined by lung-to-body weight ratios and in vivo proton magnetic resonance imaging. Although hyperoxia exposure increased lung GSH concentrations in all groups, OTC supplementation was effective for increasing lung GSH concentration in rats fed the 0.5% protein diet. This study demonstrated that oral administration of OTC to wasting malnourished rats is an effective procedure to increase GSH concentration rapidly in target organs such as lung, and that daily supplementation of a low dose of OTC has a sustained effect to protect against pulmonary oxygen toxicity during 4 days of hyperoxia exposure.
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PMID:Elevation of lung glutathione by oral supplementation of L-2-oxothiazolidine-4-carboxylate protects against oxygen toxicity in protein-energy malnourished rats. 152 40

Several investigators have implicated depletion of glutathione (GSH) and production of reactive oxygen intermediates (ROIs) in the regulation of the human immunodeficiency virus (HIV). We have shown directly that N-acetylcysteine (NAC) blocks HIV expression in chronic and acute infection models, and HIV replication in normal peripheral blood mononuclear cells. NAC is a cysteine prodrug which maintains intracellular thiol levels during oxidative stress and replenishes depleted GSH. The observed antiviral effect of NAC is due to inhibition of viral stimulation by ROIs, which are produced in response to inflammatory cytokines. We have also shown that HIV-infected individuals have decreased intracellular GSH levels in their circulating T cells. Since GSH is the major protection against the production of ROIs, we hypothesize that the observed decrease is due to a chronic oxidative stress induced by continual exposure to elevated levels of inflammatory cytokines. Together, these results provide a rationale for clinical trials testing the efficacy of GSH-replenishing drugs such as NAC in the treatment of AIDS. NAC is different than many other antiviral drugs in that it inhibits host-mediated stimulation of viral replication arising in normal immune responses, and may thereby extend latency. In addition, it inhibits the action of inflammatory cytokines which may mediate cachexia, thereby raising the possibility that it may alleviate the deleterious wasting that accompanies late stage AIDS.
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PMID:N-acetylcysteine: a new approach to anti-HIV therapy. 154 Apr 8

The blood glutathione (GSH) concentration was measured in 25 severely malnourished children and compared with a group of normal adults. In children with marasmus GSH (3.3 +/- 0.7 mg/gHb) was not different from normal (2.9 +/- 0.4 mg/gHb). However there was a highly significant decrease in all forms of oedematous malnutrition, kwashiorkor (1.5 +/- 0.4 mg/gHb) and marasmic kwashiorkor (1.7 +/- 0.7 mg/gHb). There was no relationship between wasting or stunting and blood GSH.
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PMID:Blood glutathione in severe malnutrition in childhood. 311 Oct 27

It has become widely recognized that glycine (Gly) depletion predisposes isolated proximal tubules (PT) to necrotic cell damage induced by diverse insults and that Gly replacement in vitro is highly cytoprotective. However, the effectiveness of supplementation with Gly in vivo, where blood and tissue Gly normally are maintained at high levels, is incompletely defined. Our aim was to assess whether: (a) supplementation of Gly in drinking water of rats would attenuate the proximal tubule damage and the Fanconi syndrome (FS) induced by maleate (Mal), a classical proximal tubule toxin, or ifosfamide (IFO), an antineoplastic drug; and (b) to explore the mechanisms responsible for such effects, since Gly supplementation might be especially beneficial in treating the FS, where the kidney tends to waste amino acids. Rats received daily injection of Mal (2 mmol/kg) for two days without or with oral supplementation of 2% Gly. IFO, 50 mg/kg, was injected daily for five days without or with oral Gly. Control rats were injected with saline, without or with oral Gly. The results demonstrated that both Mal and IFO induced a FS characterized by wasting of amino and organic acids, glucose, and electrolytes, along with elevated plasma creatinine (Crn) and BUN, and decreased Crn clearance rate. Light microscopy revealed a necrotic lesion in the proximal tubules of the Mal group, but no necrosis after IFO. Gly strongly ameliorated the severity of renal necrosis and/or dysfunction induced by Mal or IFO, with significant decreases in total and fractional excretion of Na+, K+, PO4(3-) and glucose, decreased plasma BUN and Crn, and increased Crn clearance. Analysis of freeze-clamped cortical tissue showed substantial depletion of [Gly], [ATP] and [GSH] along with increased GSSG in Mal or IFO groups and correction of [Gly] and [ATP] with Gly supplementation, but no improvement with Gly of reduced gluthatione [GSH] or the ratio of reduced to oxidized gluthatione (GSH/GSSG). 31P-NMR analysis of the renal cortex indicated a decrease in Pi and various membrane phospholipids in Mal and IFO rats and prevention of this damage with Gly. These observations demonstrate that oral supplementation of Gly can provide protection against Mal or IFO-induced renal tubular cell dysfunction and structural damage. The lack of effect on glutathione oxidation and depletion suggests an action distal to toxin uptake and intracellular interactions, which is similar to the characteristics of Gly cytoprotection against diverse insults in vitro. The results also suggest modification by Gly of the primary toxicity of the agents and effects on phospholipid synthesis that could contribute to repair.
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PMID:Glycine attenuates Fanconi syndrome induced by maleate or ifosfamide in rats. 864 9

It has become recognized that enhancing the antioxidant defense system during the early phase of rehabilitation is important to the survival of wasting protein-energy malnourished (PEM) patients. In this study, we compared the efficacy of dietary protein replenishment and supplementation with L-2-oxothiazolidine-4-carboxylate (OTC, 3.5 mg/d), a cysteine precursor, to protect against hyperoxia-induced lung damage in PEM rats. The PEM rats were produced by feeding weanling rats a protein-deficient diet (0.5% protein) for 14 d. PEM rats were then divided in three dietary treatment groups, 0.5% protein (-Pr), 0.5% protein plus the OTC supplement (+OTC), or 15% protein (+Pr) during 4 d of either hyperoxia (85% O2) or air exposure. Increased lung-to-body weight ratios, indicative of oxidative tissue damage, were observed following exposure to hyperoxia in -Pr and +Pr rats, but not in +OTC rats, even though the OTC supplement and the 15% protein diet contained a comparable amount of cysteine. Tissue reduced glutathione (GSH) status, GSH-dependent enzyme activity and antioxidant defense enzyme activities were monitored in the lung, liver and blood during 4 d of hyperoxia exposure. OTC supplementation enhanced GSH levels significantly in the lung of PEM rats, whereas protein repletion significantly elevated blood GSH concentrations. The protective effect of OTC was not a function of changes in activity of GSH-dependent enzymes or oxygen defense enzymes in the lung. These results indicate that a short-term strategy that selectively elevates GSH levels in the lung is more effective than protein repletion in protecting against hyperoxia-induced oxidative lung damage in PEM rats.
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PMID:Selective elevation of glutathione levels in target tissues with L-2-oxothiazolidine-4-carboxylate (OTC) protects against hyperoxia-induced lung damage in protein-energy malnourished rats: implications for a new treatment strategy. 952 26

Several studies report that among the antioxidant agents used to reduce injury after myocardial ischemia/reperfusion, analogues of vitamin E (VE) seem to have a significant efficacy. Raxofelast is a potent antioxidant agent under investigation, structurally related to VE, having an excellent bioavailability and favourable physicochemical properties. We assessed raxofelast in a rat model of myocardial damage induced by 1 h of left coronary artery occlusion followed by 6 h of reperfusion. Myocardial ischemia/reperfusion produced: wide tissue necrosis (50.3+/-10.3%); membrane peroxidation, evaluated by assessing cardiac malondialdehyde (MAL) (87.8+/-15.8 nmol/g tissuev 9.53+/-2.4 nmol/g tissue) and plasma conjugated dienes (CD) (8.73+/-1.86 DeltaABS/mlv 1.61+/-0.45 DeltaABS/ml); endogenous antioxidant wasting [cardiac VE=23.5+/-10.2 nmol/g tissuev 61.4+/-13.4 nmol/g tissue, cardiac reduced glutatione (GSH)=2.15+/-1.23 micromol/g proteinv 7.34+/-0.92 micromol/g protein and cardiac superoxide dismutase (SOD)=8.9+/-4.1 U/mg proteinv 17. 5+/-4.2 U/mg protein]; depressed mean arterial blood pressure (MAP) (61.4+/-5.8 mmHgv 85.3+/-6.2 mmHg); heart rate (HR) (275+/-35 beats/minv 368+/-34 beats/min) and left-ventricular derivative developed force (LV dP/dtmax) (1050+/-187 mmHg/sv 2520+/-194 mmHg/s); and cardiac neutrophil accumulation, evaluated by assessing cardiac myeloperoxidase (MPO) (9.23+/-2.1 U/g tissuev 0.92+/-0.12 U/g tissue). Administration of raxofelast (25, 50 and 100 mg/kg i.p. 5 min after occlusion) limited myocardial necrosis (22.3+/-14.8%P<0. 005, following the highest dose), reduced lipid peroxidation (MAL=43. 5+/-14.7 nmol/g tissueP<0.001 and CD=4.01+/-2.21 DeltaABS/mlP<0.001, following the highest dose), restored the endogenous antioxidants VE (52.8+/-14.2 nmol/g tissueP<0.001, following the highest dose), SOD (14.2+/-2.7 U/mg proteinP<0.001, following the highest dose) and GSH (4.92+/-1.33 micromol/g proteinP<0.005, following the highest dose), improved hemodynamic parameters (MAP=68.1+/-5.3 mmHgP<0.05, HR=317+/-27 beats/minP<0.05, LV dP/dtmax=1427+/-143 mmHg/sP<0.05, following the highest dose) and reduced myocardial neutrophil infiltration (MPO=5.1+/-1.5 U/g tissueP<0.001, following the highest dose). These data suggest that raxofelast could be considered a useful drug to reduce myocardial infarction.
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PMID:Beneficial effect of raxofelast, an hydrophilic vitamin E analogue, in the rat heart after ischemia and reperfusion injury. 973 36

Nephrotoxicity is an important clinical side effect of the chemotherapeutic agent ifosfamide (IFO). Taurine (TAU), an antioxidant amino acid, was used in the present study to evaluate its beneficial effects against the Fanconi syndrome (FS) induced by IFO. The rationale of use of TAU was based on its reported antioxidant effect and the fact that the kidney tends to waste amino acid in IFO-induced FS. Rats received daily injection of IFO (50 mg/kg, IP) for 5 days with or without oral supplementation of 1% TAU in the drinking water for 7 days before IFO and daily thereafter. The results demonstrated that IFO induced a FS characterized by wasting off glucose, electrolytes, and organic acids, along with elevated serum creatinine and urea, and decreased creatinine clearance rate. TAU markedly ameliorated the severity of renal dysfunction induced by IFO, with a significant decrease in total and fractional excretion of Na+, K+, PO4(-3), and glucose, decreased serum creatinine, urea, and albumin, and increased creatinine clearance rate. TAU significantly improved the IFO-induced renal glutathione (GSH) depletion, renal malondialdehyde accumulation, and body weight loss. On the other hand, in Ehrlich ascites carcinoma (EAC)-bearing mice, IFO (50 mg/kg/day, IP on days 1-4 and 15-18) demonstrated antitumor activity as a single agent. No reduction in IFO activity was observed with the supplementation of TAU (1%) in the drinking water. Furthermore, the use of TAU not only maintained high IFO antitumor activity but also was associated with lower toxicity as manifested by less body weight loss and less mortality rate of IFO therapy compared with IFO when given alone. These observations demonstrate that oral supplementation of TAU can protect against IFO-induced renal dysfunction and maintain the antitumor activity of IFO.
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PMID:Taurine attenuates fanconi syndrome induced by ifosfamide without compromising its antitumor activity. 1006 69

The mechanism of wasting, as it occurs in malignant diseases and various etiologically unrelated conditions, is still poorly understood. We have, therefore, studied putative cause/effect relationships in a murine model of cancer cachexia, C57BL/6 mice bearing the fibrosarcoma MCA-105. The plasma of these mice showed decreased albumin and increased glutamate levels, which are typically found in practically all catabolic conditions. Skeletal muscles from tumor-bearing mice were found to have an abnormally low mitochondrial respiratory chain activity (mito.RCA) and significantly decreased glutathione (GSH) levels. The decrease in mito.RCA was correlated with an increase in the i.m. GSH disulfide/GSH ratio, the plasma cystine/thiol ratio, and the GSH disulfide/GSH ratio in the bile. This is indicative of a generalized shift in the redox state extending through different body fluids. Treatment of tumor-bearing mice with ornithine, a precursor of the radical scavenger spermine, reversed both the decrease in mito.RCA and the change in the redox state, whereas treatment with cysteine, a GSH precursor, normalized only the redox state. Treatment of normal mice with difluoromethyl-ornithine, a specific inhibitor of ornithine decarboxylase and spermine biosynthesis, inhibited the mito.RCA in the skeletal muscle tissue, thus illustrating the importance of the putrescine/spermine pathway in the maintenance of mito.RCA. Ornithine, cysteine, and N-acetyl-cysteine (NAC) also reconstituted the abnormally low concentrations of the GSH precursor glutamate in the skeletal muscle tissue of tumor-bearing mice. Higher doses, however, enhanced tumor growth and increased the plasma glucose level in normal mice. In the latter, cysteine and NAC also decreased i.m. catalase and GSH peroxidase activities. Taken together, our studies on the effects of ornithine, cysteine, and NAC illuminate some of the mechanistic pathways involved in cachexia and suggest targets for therapeutic intervention.
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PMID:Differential reconstitution of mitochondrial respiratory chain activity and plasma redox state by cysteine and ornithine in a model of cancer cachexia. 1041 20

The effect of thymoquinone (TQ), the main constituent of the Nigella sativa L. oil, on ifosfamide (IFO)-induced Fanconi syndrome (FS) and its antitumor activity were investigated in rats and mice, respectively. In rats, a daily injection of IFO (50 mg/kg per day, i.p.) for 5 days induced a FS characterized by wasting off glucose, electrolytes and organic acids, along with elevated serum creatinine and urea, as well as decreased creatinine clearance rate. Administration of TQ with the drinking water of rats, (5 mg/kg per day) for 5 days before and during IFO treatment, ameliorated the severity of IFO-induced renal damage. TQ significantly improved IFO-induced phosphaturia, glucosuria, elevated serum creatinine and urea, and significantly normalized creatinine clearance rate. Moreover, TQ significantly prevented IFO-induced renal glutathione (GSH) depletion and lipid peroxide accumulation. In mice bearing Ehrlich ascites carcinoma (EAC) xenograft, TQ (10 mg/kg per day) administered in drinking water significantly enhanced the antitumor effect of IFO (50 mg/kg per day, i.p. on days 1-4 and 15-18). Furthermore, mice treated with IFO in combination with TQ showed less body weight loss and mortality rate compared to IFO single therapy. These observations demonstrate that TQ may improve the therapeutic efficacy of IFO by decreasing IFO-induced nephrotoxicity and improving its antitumor activity.
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PMID:Thymoquinone attenuates ifosfamide-induced Fanconi syndrome in rats and enhances its antitumor activity in mice. 1061 76

Redox mechanims play important roles in replication of human immunodeficiency virus type 1 (HIV-1) and cellular susceptibility to apoptosis signals. Viral replication and accelerated turnover of CD4+ T cells occur throughout a prolonged asymptomatic phase in patients infected by HIV-1. Disease development is associated with steady loss of CD4+ T cells by apoptosis, increased rate of opportunistic infections and lymphoproliferative diseases, disruption of energy metabolism, and generalized wasting. Such pathological states are preceded by: (i) depletion of intracellular antioxidants, glutathione (GSH) and thioredoxin (TRX), (ii) increased reactive oxygen species (ROS) production, and (iii) changes in mitochondrial transmembrane potential (deltapsi(m)). Disruption of deltapsi(m) appears to be the point of no return in the effector phase of apoptosis. Viral proteins Tat, Nef, Vpr, protease, and gp120, have been implicated in initiation and/or intensification of oxidative stress and disruption of deltapsi(m). Redox-sensitive transcription factors, NF-kappaB, AP-1, and p53, support expression of viral genes and proinflammatory lymphokines. ROS regulate apoptosis signaling through Fas, tumor necrosis factor (TNF), and related cell death receptors, as well as the T-cell receptor. Oxidative stress in HIV-infected donors is accompanied by increased glucose utilization both on the cellular and organismal levels. Generation of GSH and TRX from their corresponding oxidized forms is dependent on NADPH provided through the pentose phosphate pathway of glucose metabolism. This article seeks to delineate the genetic and metabolic bases of HIV-induced oxidative stress. Such understanding should lead to development of effective antioxidant therapies in HIV disease.
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PMID:Genetic and metabolic control of the mitochondrial transmembrane potential and reactive oxygen intermediate production in HIV disease. 1122 68


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