Effect of glutamine on the initiation and promotion phases of DMBA-induced mammary tumor development

BACKGROUND: Oral glutamine (GLN) has been shown to up-regulate tissue glutathione (GSH), augment natural killer (NK) cell activity, and prevent tumor growth in an implantable breast cancer model (MTF-7). We hypothesized that dietary GLN would likewise antagonize the induction or promotion of tumor formation by 7,12-dimethylbenz[a]anthracene (DMBA) via up-regulation of GSH or augmentation of NK activity. METHODS: At age 55 days, 81 Sprague-Dawley rats were gavaged with a one-time dose of 80 mg/kg DMBA, time 0. Rats were randomized into 3 groups (GLN+DMBA, Freamine [FA]+DMBA, water (H2O)+DMBA), pair-fed chow, and gavaged with 1.0 g/kg/day GLN or isonitrogenous amount of FA or H2O for the indicated times: PreFed (-1 to + 16 weeks), Short-Fed (-1 to + 1 weeks) and PostFed (+ 1 to +16 weeks). After 16 weeks, rats were killed and examined for mammary tumors, blood was assayed for GLN and GSH content, and spleens were assayed for NK cytotoxicity. RESULTS: Over the 4-month study period, there was no significant difference in tumorigenesis between FA and H2O groups, regardless of timing of feeding and amino acid diet, except GLN. In Pre- and PostFed GLN groups, there was no significant difference between groups, but there were significant decreases in tumorigenesis in GLN groups compared with either FA or H2O groups. However, in the Short-Fed group, there was no significant difference in tumorigenesis from the GLN, FA, or H2O groups. CONCLUSIONS: Continuously supplemented GLN significantly reduced DMBA-induced breast cancer growth when compared with the non-GLN-supplemented and Short-Fed supplemental GLN groups. Furthermore, GLN appears to have its primary effect on promotion and not initiation of tumor formation. This decreased tumor formation was associated with significantly higher arterial GLN and GSH levels and NK activity at killing in the GLN+DMBA group. Protein in the presentation of FA did not promote or prevent tumor growth. These data indicate that GLN may be useful in the chemoprevention of breast cancer.     

Effect of glutamine on gut glutathione fractional release in the implanted tumor model

Cancer and its treatments cause a marked depletion of glutamine (GLN). However, dietary GLN can restore this loss and improve the outcomes of the treatments. The reasons behind this need to be investigated. GLN is suggested to involve in glutathione (GSH) synthesis. Fast-growing tumors alter gut GLN metabolism, but the effect of tumor growth on gut GSH release remains unknown. We hypothesized that gut GSH release would decrease in the tumor-bearing host and this downregulation would be antagonized by supplemental GLN. Female Fisher-344 rats were randomized to the groups: GLN + TUMOR, Freamine (FA) + TUMOR, GLN + SHAM, and FA + SHAM. The rats were implanted with MTF-7 mammary tumors as tumor-bearing groups, whereas the rats were sham operated as control groups. The rats were pair fed chow, gavaged with 1 g/kg/day GLN or an isonitrogenous FA. Tumor growth, blood and gut mucosa GLN, glutamate, and/or GSH were measured. The gut extractions, defined as the difference of concentrations across the gut, were calculated. Supplemental GLN enhanced the gut GLN uptake and GSH release with tumor growth and significantly increased blood and gut mucosa GLN and/or GSH concentrations. Our results demonstrate the important antioxidant role of GLN and thus may have significant implications in nutritional immune modulation in cancer patients.     

Effect of Glutamine on Gut Glutathione Fractional Release in the Implanted Tumor Model

Cancer and its treatments cause a marked depletion of glutamine (GLN). However, dietary GLN can restore this loss and improve the outcomes of the treatments. The reasons behind this need to be investigated. GLN is suggested to involve in glutathione (GSH) synthesis. Fast-growing tumors alter gut GLN metabolism, but the effect of tumor growth on gut GSH release remains unknown. We hypothesized that gut GSH release would decrease in the tumor-bearing host and this downregulation would be antagonized by supplemental GLN. Female Fisher-344 rats were randomized to the groups: GLN + TUMOR, Freamine (FA) + TUMOR, GLN + SHAM, and FA + SHAM. The rats were implanted with MTF-7 mammary tumors as tumor-bearing groups, whereas the rats were sham operated as control groups. The rats were pair fed chow, gavaged with 1 g/kg/day GLN or an isonitrogenous FA. Tumor growth, blood and gut mucosa GLN, glutamate, and/or GSH were measured. The gut extractions, defined as the difference of concentrations across the gut, were calculated. Supplemental GLN enhanced the gut GLN uptake and GSH release with tumor growth and significantly increased blood and gut mucosa GLN and/or GSH concentrations. Our results demonstrate the important antioxidant role of GLN and thus may have significant implications in nutritional immune modulation in cancer patients.     

Modulation of p53 and c-myc in DMBA-induced mammary tumors by oral glutamine

Previous studies established that oral glutamine (GLN) reduced tumor development in implantable and 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer models. This finding was associated with a decrease in tumor glutathione (GSH) levels, while maintaining normal gut, blood, and breast GSH. Alterations in GSH levels contribute to the control of apoptotic and cell cycle-regulating signaling. The aim of this study was to examine the role of dietary GLN on activation of p53 and c-myc, which play critical roles in cancer development and sensitivity to radiation and chemotherapy. Mammary gland carcinomas were induced in rats by DMBA. The rats were gavaged daily with GLN or water (controls), starting 1 wk prior DMBA-application and throughout the duration of the experiment (11 wk after DMBA). Tumor DNA was examined for mutations in p53 exons 5 and 6. Protein and mRNA levels of p53, p21(WAF1/CIP1), PTEN, IGF-IR, mdm2, and c-myc in tumors of GLN-supplemented rats were compared with those of the control rats (received water). The sequencing of p53 showed that it was wild type. Increased phosphorylation of p53, as well as higher mRNA and protein levels of p21(WAF1/CIP1), PTEN, and mdm2, and lower levels of IGF-IR were detected in tumors of GLN-supplemented rats vs. controls. Both phosphorylated c-myc and c-myc mRNA levels were reduced by GLN. The up-regulation of tumor p53 signaling and down-regulation of c-myc, in addition to previously established inhibition of Akt signaling in DMBA-breast cancer model, suggest that dietary GLN could be a useful approach for increasing the effectiveness of cancer treatment.     

Oral glutamine (AES-14) supplementation inhibits PI-3k/Akt signaling in experimental breast cancer

BACKGROUND: 7,12-dimethylbenz [a] anthracene (DMBA) administration to pubertal rats causes breast tumors and inhibits glutathione (GSH) production. Our previous results have established that oral glutamine (GLN) supplementation significantly reduced tumor development, restored the depressed GSH production, and caused a significant decrease in the circulating levels of insulinlike growth factor-1 (IGF-1). The present study was designed to investigate the involvement of the IGF-1-activated phosphatidylinositol 3 kinase (PI-3K)/Akt apoptotic signaling pathway. MATERIALS AND METHODS: Forty female Sprague-Dawley rats were randomly divided into 4 groups: DMBA+GLN (n = 16), DMBA+water (n = 8), Oil+GLN (n = 8) and Oil+water (n = 8). At the age of 50 days, rats received a single dose of 100 mg/kg DMBA (n = 24) or sesame oil (n = 16) and were gavaged with a GLN suspension formulation (AES-14) or water for the duration of the entire experiment. The animals were killed 11 weeks after the DMBA application, and the levels of IGF-1, IGF-1 receptor (IGF-IR), Akt, Bcl-2 and Bad in tumorous and nontumorous breast tissue samples were measured by Western blot analysis. RESULTS: GLN supplementation resulted in a significant decrease in the levels of IGF-1, IGF-IR, Akt, and Bcl-2 in nontumorous samples. At the same time, the levels of pro-apoptotic protein Bad were significantly elevated. The samples collected from tumor tissues showed lower levels of IGF-1, Akt, Bcl-2, Bad, and IGF-IR in comparison with nontumorous tissues. CONCLUSIONS: GLN supplementation inhibited the PI-3K/Akt pathway that is thought to be important in increasing cell survival during tumorigenesis. These results are in agreement with our hypothesis that GLN counteracts the effects of DMBA and blocks carcinogenesis in vivo.     

Iron deficiency alters DMBA-induced tumor burden and natural killer cell cytotoxicity in rats.

Natural killer (NK) cell activity is impaired in iron-deficient rats. Natural killer cells destroy tumor cells; therefore, iron-deficient rats may be less able to combat cancer growth. Natural killer cell cytotoxicity, both basal and interferon gamma (IFN gamma)-stimulated, was studied in moderately and severely iron-deficient rats challenged with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Female weanling rats were fed ad libitum semipurified diets containing 8, 13 or 42 mg Fe/kg. A pair-fed group was fed the 42 mg Fe/kg diet at the level consumed by the 8 mg Fe/kg group. Following 6 wk of dietary treatment, DMBA-treated rats received a single intragastric dose of DMBA. Dietary treatment was continued. Rats were killed at 1, 4, 8, 14 and 20 wk post-DMBA treatment. Natural killer cell cytotoxicity (both basal and IFN gamma-stimulated) was analyzed. Feeding the 13 mg Fe/kg diet resulted in lower NK cell activity (P = 0.006) and greater tumor burden (P = 0.045) and tumor incidence. Interferon gamma treatment relieved the lower NK cell cytotoxicity observed in moderate iron deficiency. Feeding the 8 mg Fe/kg diet impaired NK cell activity (P = 0.006), but tumor burden and incidence were less than in moderate iron deficiency. In this model, iron deficiency, particularly moderate iron deficiency, contributed to cancer development and compromised NK cell cytotoxicity.     

Bolus oral glutamine protects rats against CPT-11-induced diarrhea and differentially activates cytoprotective mechanisms in host intestine but not tumor

Dietary glutamine has been suggested to preserve structural and functional integrity of the gut and high dose bolus glutamine has been hypothesized to protect against potentially fatal endotoxic shock, hyperthermic stress, and side effects of chemotherapy. In this study, we aimed to relate the ability of high dose oral bolus glutamine to mitigate the severe diarrhea induced by 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin (CPT-11) chemotherapy to specific cytoprotective mechanisms [heat shock response, glutathione (GSH)] in gut and tumor tissues. Female rats bearing Ward colon tumor received CPT-11 (125 mg x kg(-1) x d(-1)x 3 d) with or without an oral glutamine bolus (0.75 g/kg) administered 30 min prior to each CPT-11 dose. Glutamine reduced incidence and severity of late-onset diarrhea following CPT-11 treatment (P < 0.05) and was associated with potentially beneficial and protective responses in the colon: 1) a 3.1- to 7.2-fold increase of heat shock protein (Hsp)25,-70, and -90alpha (P < 0.05); 2) increased reduced GSH (rGSH):oxidized GSH ratio (P < 0.05); 3) prevention of upregulated activity of a key bacterial enzyme (beta-glucuronidase) in the cecal content that mediates CPT-11 intestinal toxicity (P < 0.05); and 4) increased proportions of CD3+CD8+ lymphocytes and memory CD8+ subset in mesenteric lymph nodes following CPT-11 therapy. By contrast, glutamine treatment did not alter CPT-11's antitumor activity, the amino acid concentrations, Hsp expression, or the ratio of rGSH:oxidized GSH in the tumor. Our data demonstrate a striking dichotomy in the response of tumor and host to oral glutamine administration, concurring with the concept that this nutrient may favorably alter the balance between the host and tumor.     

Changes in selenium and antioxidant status during DMBA-induced mammary carcinogenesis in rats

Female weanling Sprague-Dawley rats were used to examine the changes that occurred in selenium and antioxidant status during the development of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. Animals were fed an AIN-76 diet, modified to contain 20% fat (3:1 wt/wt, lard:corn oil) and 0.1, 0.035, 0.1, 1.0, 2.0 or 4.0 mg Se/kg diet. At wk 5, rats in groups 2-6 were administered by intragastric tube 4.32 mg of DMBA dissolved in corn oil. Control rats received corn oil only. A blood sample was removed from the tail vein and analyzed for selenium-dependent glutathione peroxidase (Se-GSHPx) and superoxide dismutase (SOD) activity at wk 5, and every 4 wk until wk 25. At the end of the experiment, rats were classified by tumor status, and each diet group was subdivided into two groups: those rats remaining free of tumors for 25 wk and those with tumors. DMBA treatment caused an initial decrease in erythrocyte SeGSHPx and SOD activity compared to untreated control rats. SeGSHPx activity in rats with tumors remained lower than controls, while SeGSHPX activity increased in rats with no tumors. These changes, however, were not associated with any changes in lipid peroxidation.     

Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 y

BACKGROUND: Animal studies showed that dietary flaxseed oil [rich in the n-3 polyunsaturated fatty acid alpha-linolenic acid (ALA)], evening primrose oil [rich in the n-6 polyunsaturated fatty acid gamma-linolenic acid (GLA)], and fish oil [rich in the long-chain n-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] can decrease natural killer (NK) cell activity. There have been no studies of the effect on NK cell activity of adding these oils to the diet of humans. OBJECTIVE: Our objective was to determine the effect of dietary supplementation with oil blends rich in ALA, GLA, arachidonic acid (AA), DHA, or EPA plus DHA (fish oil) on the NK cell activity of human peripheral blood mononuclear cells. DESIGN: A randomized, placebo-controlled, double-blind, parallel study was conducted. Healthy subjects aged 55-75 y consumed 9 capsules/d for 12 wk; the capsules contained placebo oil (an 80:20 mix of palm and sunflower seed oils) or blends of placebo oil and oils rich in ALA, GLA, AA, DHA, or EPA plus DHA. Subjects in these groups consumed 2 g ALA, 770 mg GLA, 680 mg AA, 720 mg DHA, or 1 g EPA plus DHA (720 mg EPA + 280 mg DHA) daily, respectively. Total fat intake from the capsules was 4 g/d. RESULTS: The fatty acid composition of plasma phospholipids changed significantly in the GLA, AA, DHA, and fish oil groups. NK cell activity was not significantly affected by the placebo, ALA, GLA, AA, or DHA treatment. Fish oil caused a significant reduction (mean decline: 48%) in NK cell activity that was fully reversed by 4 wk after supplementation had ceased. CONCLUSION: A moderate amount of EPA but not of other n-6 or n-3 polyunsaturated fatty acids can decrease NK cell activity in healthy subjects.     

Inhibitory effects of combination of lycopene and genistein on 7,12- dimethyl benz(a)anthracene-induced breast cancer in rats

Breast cancer is one of the most common cancers in women. Carotenoids and soy isoflavones have been postulated to have breast cancer preventive effects. We investigated the potential preventive effects of lycopene and genistein, alone and in combination, on breast cancer development in female Wistar rats treated with 7,12-dimethylbenz[a]anthracene (DMBA), a carcinogen known to induce breast tumors. Mammary carcinogenesis was initiated by a single, oral gavage of DMBA (80 mg/kg body weight) at 55 days of animal age. Fifty female Wistar rats were divided into 5 experimental groups having 10 animals per group: Group 1 (normal control), Group 2 (DMBA control), Group 3 (DMBA + lycopene), Group 4 (DMBA + genistein), and Group 5 (DMBA + lycopene and genistein). Rats were fed either lycopene (20 mg /kg bw) or genistein (2 mg /kg bw) by oral gavage (3 times per week) starting 2 wk prior to DMBA injection. Treatment was continued for 20 wk. Rats treated with DMBA developed mammary tumors with 100% tumor incidence during the 20-wk study. Inhibition of mammary cancer incidence by lycopene (70%), genistein (60%) and their combination (40%) was observed. Tumor weight decreased by 48%, 61%, and 67%, and mean tumor volume decreased by 18%, 35%, and 65% with lycopene, genistein, and lycopene + genistein, respectively (P < 0.01 for the combination). The proportions of adenocarcinoma masses decreased with lycopene and genistein combination (P < 0.05). Administration of lycopene and genistein combination suppressed breast cancer development and was associated with a decrease in MDA, 8-isoprostane, and 8-OhdG levels and with an increase in serum lycopene and genistein levels. Animals administered DMBA developed breast cancer, which was associated with increased expression of Bcl-2 and decreased expression of Bax, caspase 3, and caspase 9 in mammary tissues. Administration of genistein and lycopene in combination was more effective in inhibiting DMBA-induced breast tumors and modulating the expression of apoptosis associated proteins than the administration of each agent alone. Our results suggest that lycopene and genistein are potent antioxidants and, when given in combination, offer maximum protection against DMBA-induced mammary carcinogenesis.     

Withania somnifera root extract prevents DMBA-induced squamous cell carcinoma of skin in Swiss albino mice

The chemopreventive effect of Withania somnifera hydroalcoholic root extract (WSRE) on 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin cancer was investigated in Swiss albino mice. The skin lesions were induced by the twice-weekly topical application of DMBA (100 nmol/ 100 microliters acetone) for 8 wk on the shaved back of mice. WSRE was administered at the maximal tolerated dose of 400 mg/kg p.o. three times per week on alternate days 1 wk before DMBA and continued for 24 wk thereafter. The results of the study revealed a significant decrease in incidence and average number of skin lesions in mice compared with DMBA alone at the end of Week 24. Biochemical parameters were assessed in the lesions of WSRE-treated and untreated control mice. A significant impairment was noticed in the levels of reduced glutathione, malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase in skin lesions of DMBA-treated control mice compared with vehicle-treated mice. These parameters were returned to near normal by administration of WSRE to DMBA-treated mice. The above findings were supported by histopathological studies. From the present study, it can be inferred that WRSE possesses potential chemopreventive activity in this experimental model of cancer. The chemopreventive activity may be linked to the antioxidant/free radical-scavenging constituents of the extract. The anti-inflammatory and immunomodulatory properties of WSRE are also likely to contribute to its chemopreventive action.     

Inhibitory Effects of Combination of Lycopene and Genistein on 7,12- Dimethyl Benz(a)anthracene-Induced Breast Cancer in Rats

Breast cancer is one of the most common cancers in women. Carotenoids and soy isoflavones have been postulated to have breast cancer preventive effects. We investigated the potential preventive effects of lycopene and genistein, alone and in combination, on breast cancer development in female Wistar rats treated with 7,12-dimethylbenz[a]anthracene (DMBA), a carcinogen known to induce breast tumors. Mammary carcinogenesis was initiated by a single, oral gavage of DMBA (80 mg/kg body weight) at 55 days of animal age. Fifty female Wistar rats were divided into 5 experimental groups having 10 animals per group: Group 1 (normal control), Group 2 (DMBA control), Group 3 (DMBA + lycopene), Group 4 (DMBA + genistein), and Group 5 (DMBA + lycopene and genistein). Rats were fed either lycopene (20 mg /kg bw) or genistein (2 mg /kg bw) by oral gavage (3 times per week) starting 2 wk prior to DMBA injection. Treatment was continued for 20 wk. Rats treated with DMBA developed mammary tumors with 100% tumor incidence during the 20-wk study. Inhibition of mammary cancer incidence by lycopene (70%), genistein (60%) and their combination (40%) was observed. Tumor weight decreased by 48%, 61%, and 67%, and mean tumor volume decreased by 18%, 35%, and 65% with lycopene, genistein, and lycopene + genistein, respectively (P < 0.01 for the combination). The proportions of adenocarcinoma masses decreased with lycopene and genistein combination (P < 0.05). Administration of lycopene and genistein combination suppressed breast cancer development and was associated with a decrease in MDA, 8-isoprostane, and 8-OhdG levels and with an increase in serum lycopene and genistein levels. Animals administered DMBA developed breast cancer, which was associated with increased expression of Bcl-2 and decreased expression of Bax, caspase 3, and caspase 9 in mammary tissues. Administration of genistein and lycopene in combination was more effective in inhibiting DMBA-induced breast tumors and modulating the expression of apoptosis associated proteins than the administration of each agent alone. Our results suggest that lycopene and genistein are potent antioxidants and, when given in combination, offer maximum protection against DMBA-induced mammary carcinogenesis.     

Lack of an influence of dietary fat on murine natural killer cell activity

The influence of the degree of saturation and the concentration of dietary fat on murine natural killer (NK) cell activity was investigated using C3H/HeN and C57BL/6N mice. Mice were fed purified diets containing either 0% fat (fat free), 5 or 20% safflower oil or 5 or 20% palm oil. Safflower oil and palm oil were used because they are comparable in carbon chain length but vary in the amount of linoleic acid [18:2(n-6)]. Cytotoxicity of splenic NK cells from mice stimulated or unstimulated by the interferon inducer poly I:C was measured against either the YAC-1 lymphoma or line 168 mammary tumor targets. The number of asialo GM1+ cells was not influenced by concentration or degree of saturation of dietary fat. Generally, dietary fat had no consistent influence on NK cell cytotoxicity of spleen cells from either the high responder C3H/HeN mice or the moderate responder C57BL/6N mice against either tumor target. The level of 18:2(n-6) in NK cell-enriched splenic lymphocytes increased with greater levels of dietary safflower oil. Nevertheless, there appeared to be no correlation between lymphocyte fatty acid composition and NK cell cytotoxic capabilities. Therefore, the concentration of dietary safflower or palm oil, and thus 18:2 (n-6), did not appear to effect the number or activity of murine NK cells.     

Effects of oral supplementation with glutamine and alanyl-glutamine on glutamine,glutamate, and glutathione status in trained rats and subjected to long-duration exercise

ObjectiveWe investigated the effect of supplementation with the dipeptide L-alanyl-L-glutamine (DIP) and a solution containing L-glutamine and L-alanine, both in the free form, on the plasma and tissue concentrations of glutamine, glutamate, and glutathione (GSH) in rats subjected to long-duration exercise.MethodsRats were subjected to sessions of swim training. Twenty-one days before sacrifice, the animals were supplemented with DIP (1.5 g/kg, n = 6), a solution of free L-glutamine (1 g/kg) and free L-alanine (0.61 g/kg; GLN + ALA, n = 6), or water (CON, n = 6). Animals were sacrificed before (TR, n = 6) or after (LD, n = 6) long-duration exercise. Plasma concentrations of glutamine, glutamate, glucose, and ammonia and liver and muscle concentrations of glutamine, glutamate, and reduced and oxidized (GSSG) GSH were measured.ResultsHigher concentrations of plasma glutamine were found in the DIP-TR and GLN + ALA-TR groups. The CON-LD group showed hyperammonemia, whereas the DIP-LD and GLN + ALA-LD groups exhibited lower concentrations of ammonia. Higher concentrations of glutamine, glutamate, and GSH/GSSG in the soleus muscle and GSH and GSH/GSSG in the liver were observed in the DIP-TR and GLN + ALA-TR groups. The DIP-LD and GLN + ALA-LD groups exhibited higher concentrations of GSH and GSH/GSSG in the soleus muscle and liver compared with the CON-LD group.ConclusionChronic oral administration of DIP and free GLN + ALA before long-duration exercise represents an effective source of glutamine and glutamate, which may increase muscle and liver stores of GSH and improve the redox state of the cell.     

The effect of diet, exercise and 7,12-dimethylbenz(a)anthracene on food intake, body composition and carcass energy levels in virgin female BALB/c mice

This study investigated the effect of diet, exercise and , 7,12-dimethylbenz(a)anthracene (DMBA), a mammary-tumor carcinogen, on food intake, energy consumption, body weight and body composition in virgin female BALB/c mice. Interactions were examined among three diet conditions (standard AIN-76A, restricted AIN-76A and high fat AIN-76A diet), two exercise conditions (with and without treadmill exercise) and two treatment conditions (carcinogen or corn oil sham). Mice were randomized to one of 12 groups at 6 wk of age; beginning at 8 wk of age, all mice received either 7,12-dimethylbenz(a)anthracene (1 mg/0.2 mL corn oil) or 0.2 mL of corn oil via gastric tube once each week for six consecutive weeks. Exercise in a rotating-drum treadmill was initiated at 10 wk of age and was increased to a final rate of 6 m/min for 60 min, 5 d/wk. Mice were killed at 24 wk of age, confirmed to be tumor-free and analyzed for protein and fat content, from which body energy was calculated. Energy consumption was highest in the standard diet-fed groups followed by the high fat diet-fed groups and the restricted diet-fed groups. The groups fed the standard diet and restricted diet had similar body weight and carcass energy. Exercise or DMBA treatment generally reduced food consumption, energy intake, body weight and carcass energy. In summary, diet, exercise and DMBA all had pronounced effects on energy consumption, which in turn affected body composition. These treatments may influence expression of breast cancer via their effects on body composition.     

Plasma taurine concentrations increase after enteral glutamine supplementation in trauma patients and stressed rats

BACKGROUND: Taurine is a unique amino acid with antioxidant and osmolytic properties. Glutamine serves as the preferred fuel for the gut, liver, and immune cells and as a precursor for antioxidants. Trauma patients have low glutamine concentrations. OBJECTIVES: We investigated the effect of glutamine-enriched enteral nutrition on plasma taurine concentrations in patients with severe trauma (injury severity score >20). Additionally, plasma taurine concentrations and organ fluxes were studied in a stressed rat model. DESIGN: Twenty-nine patients with multiple trauma received glutamine-enriched nutrition and 31 patients received isocaloric, isonitrogenous control solution for 5 d. Plasma taurine and glutamine concentrations were measured. Male Wistar rats (250-300 g) received a glutamine-enriched diet (12%, by wt) or a control solution for 2 wk. Plasma taurine concentrations were measured. Taurine fluxes and fractional extraction rates in the liver, kidneys, and gut were assessed with a radioactive microsphere technique. RESULTS: Both patient groups had low taurine concentrations on day 1. From day 3 onward, the glutamine-fed patients had significantly higher taurine concentrations. Rats fed a glutamine-enriched diet had significantly higher plasma taurine concentrations than did the controls. A high taurine uptake was found in the liver, kidneys, and gut of the glutamine-fed rats. Fractional extraction rates were not significantly different between the rat groups. CONCLUSIONS: Glutamine enrichment increases plasma taurine in trauma patients and in stressed rats. Because of increased availability, organ fluxes showed a higher taurine uptake in the liver, kidneys, and gut. The reduction in morbidity with glutamine enrichment could be explained in part by increased taurine availability.     

Influence of prenatal iron and zinc supplements on supplemental iron absorption, red blood cell iron incorporation, and iron status in pregnant Peruvian women

BACKGROUND: It is estimated that 60% of pregnant women worldwide are anemic. OBJECTIVE: We aimed to examine the influence of iron status on iron absorption during pregnancy by measuring supplemental iron absorption, red blood cell iron incorporation, and iron status in pregnant women. DESIGN: Subjects were 45 pregnant Peruvian women (33+/-1 wk gestation), of whom 28 received daily prenatal supplements containing 60 mg Fe and 250 microg folate without (Fe group, n = 14) or with (Fe+Zn group, n = 14) 15 mg Zn, which were were consumed from week 10 to 24 of gestation until delivery. The remaining 17 women (control) received no prenatal supplementation. Iron status indicators and isotopes were measured in maternal blood collected 2 wk postdosing with oral (57Fe) and intravenous (58Fe) stable iron isotopes. RESULTS: Maternal serum ferritin and folate concentrations were significantly influenced by supplementation (P < 0.05). Serum iron was also significantly higher in the Fe than in the Fe+Zn (P < 0.03) or control (P < 0.001) groups. However, the supplemented groups had significantly lower serum zinc concentrations than the control group (8.4+/-2.3 and 10.9+/-1.8 micromol/L, respectively, P < 0.01). Although percentage iron absorption was inversely related to maternal serum ferritin concentrations (P = 0.036), this effect was limited and percentage iron absorption did not differ significantly between groups. CONCLUSIONS: Because absorption of nonheme iron was not substantially greater in pregnant women with depleted iron reserves, prenatal iron supplementation is important for meeting iron requirements during pregnancy.     

Inflammation rather than nutritional depletion determines glutamine concentrations and intestinal permeability

AIM: Nutritional depletion has been correlated with low plasma and mucosal glutamine concentrations and with increased intestinal permeability. Since nutritional depletion often is associated with (chronic) inflammatory stress, this study was designed to establish the influence of depletion and inflammation on glutamine concentrations and gut barrier function. METHODS: Anthropometric parameters were calculated from 26 patients who required artificial nutrition. Glutamine concentrations in plasma and gut mucosa, gut permeability and mucosal morphology were assessed. For determination of the degree of inflammation erythrocyte sedimentation rates and (pre)albumin concentrations were measured. On the basis of these parameters patients were divided into two groups having significant inflammatory stress or not. Similarly, a depleted and a non-depleted group was formed based on percentage ideal body weight, fat-free mass index (FFMI) and percentage weight loss. Glutamine concentrations, gut permeability and villus morphology were compared between the groups. RESULTS: The presence of inflammatory activity had significant negative effects on glutamine concentrations in contrast to the presence or absence of nutritional depletion. Similarly, intestinal permeability increased during active inflammation but not in depleted patients. FFMI but not inflammation was related to villus height. CONCLUSIONS: The presence of inflammation significantly affects glutamine concentrations and gut permeability, in contrast to the presence of depletion of body cell mass per se. On the other hand, villus morphology is not influenced by changes in systemic inflammatory activity whereas nutritional status possibly does affect villus height.     

Impact of oral L-glutamine on glutathione, glutamine, and glutamate blood levels in volunteers

OBJECTIVE: We investigated the effect of glutamine supplementation on plasma glutamine (Gln), glutamate (Glu), and whole-blood glutathione (GSH) concentrations in human volunteers. METHODS: Subjects first adapted to a standard diet with known intakes of protein, total GSH, cysteine, methionine, and total Glu (Glu values include Glu and Gln) for 3 d. Plasma Gln, Glu, and whole-blood GSH levels were then measured at 4-h intervals over 24 h. Supplemental oral Gln (0.3 g x kg(-1) x d(-1)) was ingested for 10 d and then 24-h plasma levels of Gln, Glu, and whole-blood GSH were measured. RESULTS: The plasma concentrations of Glu (116%; P = 0.006) and Gln (20%; P = 0.046) were significantly higher, whereas concentrations of GSH were significantly lower (37%; P = 0.00091) after oral Gln supplementation. CONCLUSION: Oral Gln increases Glu and Gln levels in plasma of healthy subjects but does not increase GSH red cell (whole-blood) levels. Thus, GSH biosynthesis and preservation of GHS stores in red blood cells may involve rate-limiting substrates other than Gln.     

The Alleviation of Gut Microbiota-Induced Depression and Colitis in Mice by Anti-Inflammatory Probiotics NK151, NK173, and NK175

Gut microbiota dysbiosis is strongly associated with psychiatric disorders and inflammatory bowel disease (IBD). Herein, we examined whether the fecal microbiota of IBD patients with depression (IBDD) and their gut microbiota culture (iGm) could cause depression and colitis in mice and anti-inflammatory probiotics could mitigate depression in iGm-transplanted or immobilization stress (IS)-exposed mice. Fecal microbiota transplantation (FMT) from IBDD patients, which exhibited Enterobacteriaceae-rich gut microbiota, and its gut microbiota culture (iGm) increased depression-like behaviors in mice. Their treatments heightened the blood lipopolysaccharide (LPS) level and colonic IL-1β and IL-6 expression. However, FMT from healthy volunteers or sulfasalazine treatment alleviated cGm-induced depressive-like behaviors and hippocampal and colonic inflammation in mice. Moreover, oral administration of Lactobacillus plantarum NK151, Bifidobacterium longum NK173, and Bifidobacterium bifidum NK175, which inhibited LPS-induced IL-6 expression in macrophages, alleviated cGm-induced depression-like behaviors, hippocampal NF-κB⁺Iba1⁺ cell numbers and IL-1β and IL-6 expression, blood LPS, IL-6, and creatinine levels, and colonic NF-κB⁺CD11c⁺ number and IL-1β and IL-6 expression in mice. Treatment with NK151, NK173, or NK175 mitigated immobilization stress (IS)-induced depressive-like behaviors, neuroinflammation, and gut inflammation in mice. NK151, NK173, or NK175 also decreased IS-induced blood LPS, IL-6, and creatinine levels. The transplantation of Enterobacteriaceae-rich gut microbiota can cause depression and colitis, as IS exposure, and anti-inflammatory NK151, NK173, and NK175, may alleviate stress-induced fatigue, depression, and colitis by regulating the expression of proinflammatory and anti-inflammatory cytokines through the suppression of gut bacterial LPS.