Selenium and zinc protect brain mitochondrial antioxidants and electron transport chain enzymes following postnatal protein malnutrition.

AIMS: Selenium (Se) and zinc (Zn) are trace elements required for optimal brain functions. Thus, the role of Se and Zn against protein malnutrition induced oxidative stress on mitochondrial antioxidants and electron transport chain (ETC) enzymes from rats' brain were investigated. MAIN METHODS: Normal protein (NP) and low protein (LP) rats were fed with diets containing 16% and 5% casein respectively for a period of 10weeks. Then the rats were supplemented with Se and Zn at a concentration of 0.15mgL(-1) and 227mgL(-1) in drinking water for 3weeks after which the rats were sacrificed. KEY FINDINGS: The results obtained from the study showed significant (p<0.05) increase in lipid peroxidation (LPO), ROS production, oxidized glutathione (GSSG) levels and mitochondrial swelling and significant (p<0.05) reductions in catalase (CAT) and Mn-superoxide dismutase (Mn-SOD) activities, glutathione (GSH) levels, GSH/GSSG ratio and MTT reduction as a result of LP ingestion. The activities of mitochondrial ETC enzymes were also significantly inhibited in both the cortex and cerebellum of LP-fed rats. Supplementation with either Se or Zn restored the alterations in all the parameters. SIGNIFICANCE: The study showed that Se and Zn might be beneficial in protecting mitochondrial antioxidants and ETC enzymes against protein malnutrition induced oxidative stress.

Bee pollen improves muscle protein and energy metabolism in malnourished old rats through interfering with the Mtor signaling pathway and mitochondrial activity.

Although the management of malnutrition is a priority in older people, this population shows a resistance to refeeding. Fresh bee pollen contains nutritional substances of interest for malnourished people. The aim was to evaluate the effect of fresh bee pollen supplementation on refeeding efficiency in old malnourished rats. Male 22-month-old Wistar rats were undernourished by reducing food intake for 12 weeks. The animals were then renourished for three weeks with the same diet supplemented with 0%, 5% or 10% of fresh monofloral bee pollen. Due to changes in both lean mass and fat mass, body weight decreased during malnutrition and increased after refeeding with no between-group differences (p < 0.0001). Rats refed with the fresh bee pollen-enriched diets showed a significant increase in muscle mass compared to restricted rats (p < 0.05). The malnutrition period reduced the muscle protein synthesis rate and mTOR/p70S6kinase/4eBP1 activation, and only the 10%-pollen diet was able to restore these parameters. Mitochondrial activity was depressed with food restriction and was only improved by refeeding with the fresh bee pollen-containing diets. In conclusion, refeeding diets that contain fresh monofloral bee pollen improve muscle mass and metabolism in old, undernourished rats.

Decreased insulin secretion in islets from protein malnourished rats is associated with impaired glutamate dehydrogenase function: effect of leucine supplementation.

We herein studied the role of glutamate dehydrogenase (GDH), in response to leucine (LEU) supplementation, upon insulin secretion of malnourished rats. Weaned male Wistar rats were fed normal-protein (17%) or low-protein diet (6%, LP) for 8 weeks. Half of the rats of each group were supplemented with LEU (1.5%) in the drinking water for the following 4 weeks. Gene and protein expressions, static insulin secretion, and cytoplasmic Ca(2+) oscillations were measured. Glutamate dehydrogenase messenger RNA was 58% lower in LP islets, and LEU supplementation augmented it in 28%. The LP islets secreted less insulin when exposed to 20 mmol/L LEU, 20 mmol/L LEU + 2 mmol/L glutamine (with or without 5 mmol/L aminooxyacetic acid, a branched chain aminotransferase inhibitor, or 20 µmol/L epigallocatechin gallate, a GDH inhibitor), 20 mmol/L α-ketoisocaproate, glutamine + 20 mmol/L ß-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (a GDH activator), and 22.2 mmol/L glucose. Leucine supplementation augmented insulin secretion to levels found in normal-protein islets in all the above conditions, an effect that was blunted when islets were incubated with epigallocatechin gallate. The glutamine + ß-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid-induced increased [Ca(2+)](i) and oscillations were higher than those for LP islets. Leucine supplementation normalized these parameters in LP islets. Impaired GDH function was associated with lower insulin release in LP islets, and LEU supplementation normalized insulin secretion via restoration of GDH function. In addition, GDH may contribute to insulin secretion through ameliorations of Ca(2+) handling in LP islets.

Effects of dietary medium-chain triacylglycerol on mRNA level of gluconeogenic enzymes in malnourished rats.

We have reported previously that dietary medium-chain triacylglycerol (MCT) improved serum albumin concentration and protein balance in malnourished rats. To clarify the mechanisms for this effect of MCT, hepatic messenger RNA levels of gluconeogenic enzymes, pyruvate dehydrogenase (PDH) and alanine aminotransferase (ALT) were measured in rats fed low-protein diets containing either MCT or isocaloric long-chain triacylglycerol (LCT) for 2 wk. The serum albumin concentration in rats fed the MCT diet was significantly higher compared with those fed the LCT diet. Serum free fatty acids and ketone body fraction were higher in rats fed MCT compared with those fed the LCT diet. The hepatic mRNA level of PDH was significantly lower in rats fed MCT than those fed LCT. But, there was no significant difference between the two groups in mRNA of gluconeogenic enzymes or ALT. These results suggest that ketone bodies, which are an alternative energy source and might spare blood glucose, increase by MCT feeding, and the reason for the PEM (protein-energy malnutrition)-improving effect of MCT is not caused by suppression of gluconeogenesis.

Effects of cysteine on the pharmacokinetic parameters of omeprazole in rats with protein-calorie malnutrition: partial restoration of some parameters to control levels by oral cysteine supplementation.

BACKGROUND: It has been reported that omeprazole is mainly metabolized via the hepatic cytochrome (CYP) 1A1/2, 3A1/2, and 2D1, and the expressions and mRNA levels of CYP1A2, 2C11, and 3A1/2 decreased in protein-calorie malnutrition (PCM) rats compared with controls. Interestingly, the decreased CYP1A2, 2C11, and 3A1/2 in PCM rats returned fully or partially to control levels by oral cysteine supplementation (PCMC rats). Hence, it could be expected that some pharmacokinetic parameters of omeprazole might change in PCM rats and partially restore to control levels in PCMC rats. The purpose of this study is to investigate the pharmacokinetic changes of omeprazole in PCM rats and restoration of the parameters in PCMC rats to control levels. METHODS: Omeprazole was administered intravenously (20 mg/kg) and orally (40 mg/kg) to control, PCM, and PCMC rats. RESULTS: The following pharmacokinetic parameters were changed in PCM rats and partially returned to control levels in PCMC rats: the area under the plasma concentration-time curve (AUC; 387, 762, and 539 microg min/mL for control, PCM, and PCMC rats, respectively, after intravenous [IV] administration, and the corresponding values after oral administration: 115, 304, and 201 microg min/mL), total body clearance (51.7, 25.5, and 37.1 mL/min/kg, respectively), nonrenal clearance (51.5, 25.4, and 36.1 mL/min/kg, respectively), and in vitro intrinsic clearance (0.158, 0.118, and 0.138 mL/min/mg protein). CONCLUSIONS: PCM was associated with significant changes in some omeprazole pharmacokinetics and the pharmacokinetic parameters restored to control levels by oral cysteine.

Effects of cysteine on amino acid concentrations and transsulfuration enzyme activities in rat liver with protein-calorie malnutrition.

The changes in amino acid concentrations and transsulfuration enzyme activities in liver were investigated after 4-week fed on 23% casein diet (control group) and 5% casein diet without (protein-calorie malnutrition, PCM group) or with (PCMC group) oral administration of cysteine, 250 mg/kg (twice daily, starting from the fourth week) using rats as an animal model. By supplementation with cysteine in PCM rats (PCMC group), cysteine level was elevated almost close to the control level, and glutathione (GSH), aspartic acid and serine levels were restored greater than the control levels. The measurement of transsulfuration enzyme activities exhibited that gamma-glutamylcysteine ligase (gamma-GCL) activity was up-regulated in rats with protein restriction (PCM group), and cysteine supplementation (PCMC group) down-regulated to the control level. One-week supplementation of cysteine (PCMC group) significantly down-regulated the cysteine sulfinate decarboxylase activity. These results indicate that the availability of sulfur amino acid(s) especially cysteine appears to play a role in determining the flux of cysteine between cysteine catabolism and GSH synthesis.

Prevention of c-Jun/activator protein-1 activation and microsomal epoxide hydrolase induction in the rat liver by cysteine during protein-calorie malnutrition.

Protein-calorie malnutrition (PCM), a major global health problem, arises during protein and/or energy deficit due to disease and nutritional inadequacy. To date, cellular adaptive responses and gene expression associated with PCM remain poorly understood. In view of the primary role of the liver in energy conversion, the present study was designed to investigate changes in hepatic morphology and molecular alterations during PCM. PCM caused marked decreases in the cytoplasmic eosinophilic content and nuclear shrinkage in the hepatocytes with a decrease in glutathione content. The nuclear activator protein-1 (AP-1) complex was activated in the liver of PCM rats. AP-1-binding activity of nuclear extracts produced from PCM rats was reduced by the presence of anti-c-Jun antibody. Microsomal epoxide hydrolase (mEH), a phase II detoxifying enzyme, was 4-fold induced, with a 20-fold increase in the mRNA level during PCM. In contrast to the PCM-induced changes in hepatic morphology, PCM rats supplemented with cysteine showed an increase in the GSH level and well-preserved hepatic structures with mild fat degeneration. Cysteine supplementation inhibited the activation of AP-1 and the induction of mEH in PCM rats. These results provided evidence: (i) that PCM alters liver morphology with a decrease in the glutathione level; (ii) that cysteine may serve as a key element responsible for preserving hepatic morphology and maintaining the glutathione level; and (iii) that cysteine was active in preventing the activation of AP-1 and mEH induction in the liver during PCM.

Biotin supplementation affects lymphocyte carboxylases and plasma biotin in severe protein-energy malnutrition.

We studied the effect of a supplement of biotin (10 mg/d) or a placebo under double-blind conditions on plasma biotin concentrations and lymphocyte propionyl CoA carboxylase (PCC) and pyruvate carboxylase (PC) in 22 children with severe protein-energy malnutrition (PEM) (5 with kwashiorkor, 10 with marasmus, and 7 "sugar babies"). There were significant differences between the malnourished and control subjects only for PCC, although not among the three PEM types. Six of the patients had both PC and PCC activities below the lowest of the normal control subjects; there was no correlation between biotin concentrations and carboxylase activities in individual patients. In response to biotin supplementation, the greatest change in lymphocyte carboxylase activities was detected in patients who had abnormally decreased initial carboxylase activities, but the response was not related to initial plasma biotin concentration. These results indicate that these enzyme deficiencies are the result of a nutritionally determined biotin deficiency, that carboxylases and especially PCC are better indicators of the biotin status in individual patients than is the plasma biotin concentration, and that in some malnourished patients biotin deficiency may be rate-limiting in their nutritional homeostasis.

Red blood cell antioxidant enzyme concentrations in kwashiorkor and marasmus.

Kwashiorkor may occur when an imbalance between pro- and antioxidants in malnourished children results in an excess of free radicals. The concentrations of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), reduced glutathione (GSH) and glutathione peroxidase (GPX) were measured in erythrocytes of 22 children with kwashiorkor on admission to hospital and repeated on days 5, 10 and 30 of recovery. The concentrations were compared with those in 22 children with marasmus and in 20 children who were normally nourished but had infective illness necessitating their hospitalization. CAT and SOD were similar in all groups and did not change during recovery. GSH and GPX were significantly lower in kwashiorkor than in the other groups. Concentrations of thiobarbituric acid-reactive substances (TBARS), a marker of lipid peroxidation, were significantly elevated in children with kwashiorkor. During clinical recovery, GSH but not GPX concentrations rose despite an increase in plasma selenium levels and decreased concentrations of TBARS. These findings suggest that the antioxidant status of children with kwashiorkor differs from that of well nourished and marasmic children. Whether these differences are the cause of the consequence of the clinical picture is unresolved.

Selenium status in Sudanese children with protein-calorie malnutrition.

In 68 Sudanese children with severe protein-energy malnutrition, age 1-4 years, the selenium status was investigated and the results were compared with those of healthy Sudanese and German children. The median selenium content in plasma of healthy Sudanese children (x = 59 micrograms/L) and with those of marasmus (x = 57 micrograms/L) were found to be in the same range. It was lower than in healthy German children (x = 82 micrograms/L). Patients with marasmic kwashiorkor exhibited still lower values (x = 42 micrograms/L. Within each group of malnourished children (marasmus, marasmic kwashiorkor, kwashiorkor) there were patients with low and with "normal" selenium values (taking the values of healthy German children as normal). Hair selenium values were not different between marasmic Sudanese children and healthy German children, probably due to reduced hair growth in malnourished children. Plasma glutathione peroxidase activity was reduced concomitantly with plasma selenium in the patients with protein-calorie malnutrition. There was a good correlation between plasma selenium and plasma glutathione peroxidase activity. A follow-up study showed that plasma selenium decreased during rehabilitation in those patients who had a "normal" value before treatment. This is probably due to the low selenium content of the two dietary formulae used, which contained 18 and 25 micrograms/L Se of formula,. It remains questionable whether the low selenium states and low selenium intake exhibit a healthy risk inhibiting further rehabilitation of the patients with severe protein-calorie malnutrition.

[Lipid peroxidation intensity in the liver in protein-energy deficiency]. / Intensivnost' perekisnogo okisleniia lipidov pecheni pri belkovo-énergeticheskoi nedostatochnosti.

A fall in the glutathione peroxidase, glutathione reductase activity and selenium concentration was recorded in the liver of rats given diets poor in protein. The hepatic antioxidizing activity was lowered, lipid peroxidation (LPO) was intensified which was expressed in the growth of the amount of conjugated dienes, diene ketones and malonic dialdehydes. Diets poor in protein supplemented with sodium selenite and alpha-tocopherol acetate induced a significant increase in the selenium concentration and intensified the hepatic glutathione peroxidase and glutathione reductase activity. The rise in the oxide reductase activity was attended by a decreased rate of accumulation of LPO products, their amount being significantly lower as compared to that in the animals who were not given antioxidants.

Red cell superoxide dismutase activity as an index of human copper nutrition.

Red cell superoxide dismutase (SOD) activity was evaluated as a biochemical index of copper nutrition in a double-blind study of 17 infants recovering from malnutrition and receiving marginal copper intakes. Children were paired on admission by sex, birth weight, nutritional status and antecedents of diarrhea and breast feeding. Nine served as controls receiving a copper sulfate supplement (80 micrograms/kg daily for 120 d; eight received a placebo and were supplemented only if plasma copper levels dropped below 90 micrograms/dl or on d 90 for at least 30 d. After copper supplementation there was a significant rise (paired t-test; P less than 0.05) in plasma copper (96 vs. 165 micrograms/dl); ceruloplasmin (33 vs. 50 mg/dl) and SOD (1073 vs. 1371 U/g Hb). After supplementation these values were similar to those of the controls. SOD was correlated with plasma copper (r = 0.78; P less than 0.001) and not with weight-for-age or weight-for-length. Addition of copper in vitro did not modify the SOD activity. Red cell SOD is a good marker of copper nutrition in humans and correlates well with plasma copper.

Serum 25-hydroxy-vitamin D levels in malnourished children with rickets.

Serum levels of calcium, phosphorus, alkaline phosphatase, and 25 hydroxy-vitamin D (25-OH-D3) were measured in normal and malnourished children with and without rickets. Children with rickets had clinical, biochemical, and x-ray evidence of the disease; most of them were malnourished. 25-OH-D3 levels were lower than in normal children. After treatment with vitamin D their condition improved. 25-OH-D3 levels were also found to be reduced in malnourished children without rickets. These studies show that rickets is common in malnourished children. Inadequate exposure to sunlight appears to be the factor mainly responsible for the high incidence of the disease. In addition, malnutrition perhaps contributes to the development of rickets.