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Active lymphocytes (LY) and macrophages (MPhi) are involved in the pathophysiology of rheumatoid arthritis (RA). Due to its anti-inflammatory effect, physical exercise may be beneficial in RA by acting on the immune system (IS). Thus, female Wistar rats with type II collagen-induced arthritis (CIA) were submitted to swimming training (6 weeks, 5 days/week, 60 min/day) and some biochemical and immune parameters, such as the metabolism of glucose and glutamine and function of LY and MPhi, were evaluated. In addition, plasma levels of some hormones and of interleukin-2 (IL-2) were also determined. Results demonstrate that CIA increased lymphocyte proliferation (1.9- and 1.7-fold, respectively, in response to concanavalin A (ConA) and lipopolysaccharide (LPS)), as well as macrophage H(2)O(2) production (1.6-fold), in comparison to control. Exercise training prevented the activation of immune cells, induced by CIA, and established a pattern of substrate utilization similar to that described as normal for these cells. Exercise also promoted an elevation of plasma levels of corticosterone (22.2%), progesterone (1.7-fold) and IL-2 (2.6-fold). Our data suggest that chronic exercise is able to counterbalance the effects of CIA on cells of the IS, reinforcing the proposal that the benefits of exercise may not be restricted to aerobic capacity and/or strength improvement., (2010 John Wiley & Sons, Ltd.)

1. Serotonin is a neurotransmitter that modulates several functions, such as food intake, energy expenditure, motor activity, mood and sleep. Acute exhaustive endurance exercise increases the synthesis, concentration and metabolism of serotonin in the brain. This phenomenon could be responsible for central fatigue after prolonged and exhaustive exercise. However, the effect of chronic exhaustive training on serotonin is not known. The present study was conducted to examine the effect of exhaustive endurance training on performance and serotonin concentrations in the hypothalamus of trained rats. 2. Rats were divided into three groups: sedentary rats (SED), moderately trained rats (MOD) and exhaustively trained rats (EXT), with an increase of 200% in the load carried during the final week of training. 3. Hypothalamic serotonin concentrations were similar between the SED and MOD groups, but were higher in the EXT group (P < 0.05). Performance was lower in the EXT group compared with the MOD group (P < 0.05). 4. Thus, the present study demonstrates that exhaustive training increases serotonin concentrations in the hypothalamus, together with decreased endurance performance after inadequate recovery time. However, the mechanism underlying these changes remains unknown.

1. Doxorubicin is an anti-cancer drug with well-described effects against a wide range of tumours. However, doxorubicin also exhibits dose-dependent cytotoxicity. The purpose of the present study was to determine whether chronic supplementation of creatine or a mix of vitamins C and E could increase survival and improve plasma parameters 48 h after doxorubicin treatment. 2. Rats were divided into four groups: (i) saline (control); (ii) doxorubicin treated; (iii) a creatine (0.2 g/kg per day)-supplemented group; and (iv) a vitamin C (250 mg/kg per day) and E (400 IU/kg per day)-supplemented group. After 30 days supplementation of rats with either creatine or the vitamins, one dose of doxorubicin (15 mg/kg, i.p.) was administered. 3. There was no difference in weight loss among the groups until the 3rd day after doxorubicin treatment, but the creatine- and vitamin-supplemented groups lived longer compared with the doxorubicin only treated group (6, 7 and 3 days, respectively). The doxorubicin-treated group lost 13.4% bodyweight over 3 days, whereas the creatine- and vitamin-supplemented groups lost approximately 35% 3 days after the administration of doxorubicin. Doxorubicin treatment resulted in an increase in alanine aminotransferase (ALT; P < 0.05), lactate dehydrogenase (LDH; P < 0.05), urea (P < 0.05) and creatinine (P < 0.05) compared with levels observed in the control group. Conversely, creatine supplementation promoted a partial return to control values for LDH (P < 0.05) and creatinine (P < 0.05), whereas the vitamin mix reversed the changes in ALT (P < 0.05), LDH (P < 0.05), urea (P < 0.05) and creatinine (P < 0.05). 4. In conclusion, the results of the present study indicate that the two supplementation protocols decreased the cytotoxic effects of doxorubicin and that a protective effect was more noticeable in animals supplemented with the mixture of vitamins C and E.

1. The present study sought to evaluate cardiovascular adaptations, such as blood pressure (BP), heart rate (HR) and cardiac hypertrophy, to resistance training (RT) in a rat model. 2. The training protocol consisted of four sets of 10-12 repetitions of the squat exercise performed at 65-75% of one repetition maximum (1RM) over 4 weeks. Animals were randomly divided into three groups: control (n = 8, CO), electrically stimulated (n = 8, ES) and trained (n = 8, TR; also electrically stimulated). Blood pressure and HR were measured by a direct method in conscious rats after the training period. 3. All groups began with similar 1RM and 1RM/bodyweight (BW) ratio, however, at the end of the protocol only the TR group was different from the beginning (56% and 50%, respectively; both P < 0.01). The CO and ES groups had similar values for cardiac chambers weight/BW ratio, HR and diastolic, systolic and mean BP. Left ventricular hypertrophy (LVH) determined by the left ventricle (LV) weight/BW ratio was increased in the TR group (12%) when compared to CO (P < 0.01) or ES groups (P < 0.01). No changes were found in the weights of the atrium or right ventricle. Diastolic (14%) and mean BP (13%) were lower in the TR group (P < 0.05), whereas systolic BP and HR remained unchanged. 4. Collectively these results demonstrate that the rat RT model used is associated with significant development of cardiac hypertrophy and lowering of resting BP. These cardiovascular adaptations seem to a result of the training exercise and not influenced by stress since circulating catecholamine levels and adrenal gland weights remained unchanged in all groups.

During intense exercise there is an augmented production of ammonia and IMP in the exercised muscle that could be related to the establishment of peripheral fatigue. In order to prevent this accumulation, the urea cycle in the liver eliminates ammonia in the form of urea and the skeletal muscle buffers the increase of ammonia via transamination reactions. In the present study we evaluated the effect of arginine, citrulline and ornithine supplementation, intermediates of the urea cycle, on the performance of sedentary and swimming-trained rats submitted to a single bout of exhaustive exercise. We also measured the glycogen content of the soleus and gastrocnemius muscles and of the liver, as well as the plasma concentrations of ammonia, urea, glutamine, glucose and lactate. The results indicate that arginine, citrulline and ornithine supplementation increased the flux of substrate through the reaction catalysed by glutamine synthetase, leading to increased glutamine production after an exhaustive bout of exercise, and of the mechanism involved in ammonia buffering., (Copyright 2002 John Wiley & Sons, Ltd.)

Nucleated cells are more resistant to complement-mediated cell death than anucleated cells such as erythrocytes. There are few reports concerning the metabolic response of nucleated cells subjected to sub-lethal complement attack. It is possible that the rate of utilization of specific metabolic fuels by the cell is increased to enhance cell defence. We have measured the maximum activity of hexokinase, citrate synthase, glucose 6-phosphate dehydrogenase and glutaminase in rat mesenteric lymphocytes exposed to sub-lethal concentrations of activated complement (present in zymosan-activated serum, ZAS). These enzymes were carefully selected as they indicate changes of flux in glycolysis, TCA cycle, pentose phosphate pathway and glutaminolysis, respectively. The only enzyme activity to change on exposure of lymphocytes to ZAS was glutaminase, which was enhanced approximately by two-fold. Although rates of both glutamine and glucose utilization were enhanced by exposure to ZAS, only the rate of oxidation of glutamine was increased. Complement kills anucleated cells by simple osmotic lysis. However, it is likely that some nucleated cells will display characteristics of an ordered death mechanism and we have demonstrated that the concentration of lymphocyte ATP is dramatically decreased by activated complement. Nevertheless, the extent of cell death could be significantly reduced by the addition of inhibitors of the nuclear enzyme poly (ADP-ribose) polymerase (PARP). We conclude that glutamine metabolism is not only important for lymphocyte proliferative responses but is also important for cell defence from sub-lethal concentrations of activated complement. The rapid rate of complement-induced lymphocyte death reported here is suggested to be a consequence of over-activation of the nuclear enzyme PARP and ATP depletion., (Copyright 2002 John Wiley & Sons, Ltd.)

It is commonly accepted that moderate intensity exercise is beneficial to the immune system. We tested the influence of a moderate intensity training protocol (8 weeks) upon immune system function in Wistar tumour-bearing (TB) rats. The metabolism of glucose and glutamine in lymphocytes and macrophages was assessed, together with some functional parameters (hydrogen peroxide production and lymphocyte proliferative response). These substrates were chosen since they represent the most important energetic and synthetic metabolites for these cellular types. The training protocol caused a decrease of 17.4 per cent in the production of H(2)O(2) by macrophages, as well as a decrease in glucose consumption (25 per cent) and lactate production (47.1 per cent), and an increase in the production of labelled CO(2) from the oxidation of [U-(14)C]-glucose, in TB rats. The training protocol was also able to induce changes in the maximal activity of some key enzymes in the metabolism of glucose and glutamine, a reduction of hexokinase (68.8 per cent) activity and an increase in the activity of citrate synthase (10.1 per cent) in TB rats. The training protocol increased the proliferative response of lymphocytes cultivated in the absence of mitogens (75 per cent), of those cultivated in the presence of ConA (38.2 per cent) and in the presence of LPS (45.0 per cent). These cells also showed an increase in the maximal activity of some key enzymes of the glycolytic and glutaminolytic pathways. Our data demonstrated that the training protocol was able to induce an increase in aerobic utilisation of both substrates in lymphocytes and macrophages. The training protocol was also able to prevent several changes in glucose and glutamine metabolism that are normally present in sedentary TB rats. These changes in immune cell metabolism induced by the training protocol were able to increase TB rat survival., (Copyright 2000 John Wiley & Sons, Ltd.)

Kupffer cells (KC), the liver macrophages, are able to produce PGE(2), which is involved in immune suppression and in the aggravation of cancer cachexia due to interference with lipid metabolism in the liver. Since tumour-bearing (TB) rats present high plasma epinephrine levels, and this hormone is able to affect macrophage metabolism and function, we have assessed the effect of epinephrine (5 nM) upon Kupffer cell PGE(2) production. Epinephrine induced increased production of PGE(2) both by control (3.5-fold) and TB rats (27 per cent) KC, an effect blocked by propranolol. Enhancement of cAMP content in the cells by addition of isoproterenol (0.1 microM) to the incubations, however, failed to induce the same response in the cells. Nevertheless, when phenylephrine (1 microM) was added to the incubation, a similar pattern of PGE(2) production to that observed for epinephrine was found for control and TB rat KC. We propose that the effect of epinephrine upon KC PGE(2) production is mediated by alpha-adrenergic receptors and that Ca(2+) is involved in the response, since increasing concentrations of the ion added to the incubation medium (0.25, 0.5 and 1.0 mM) enhanced the eicosanoid production, while EDTA abolished the response., (Copyright 1999 John Wiley & Sons, Ltd.)

In nucleated cells, the swelling promoted by a complement system (CS) attack is not enough to promote cell death, because unlike erythrocytes these cells are able to eliminate cytolytic complement channels from the plasma membrane, by processes that include endocytosis. Several studies have demonstrated that the resistance of nucleated cells to the injury promoted by the CS is related to the cellular metabolism. Despite this, to the present day, no study has clearly related cell survival capacity to injury by the CS to its energetic metabolic status. In macrophages, the challenge imposed by the CS provoked an increase in the total amount of glucose incorporated into fatty acids, including phospholipids and cholesterol; substrates for membrane synthesis. The inhibition of cholesterol synthesis promoted an increase of the cell death rate. These data support the importance of cholesterol metabolism for macrophage resistance to necrosis induced by the activated complement system., (Copyright 1999 John Wiley & Sons, Ltd.)

Several studies have shown that thyroid hormones are able to influence selected immune responses such as cell mediated immunity, differentiation of B lymphocytes and the activity of NK cells. These hormones can also regulate the metabolism of glucose and glutamine in rat macrophages and their effects seem to occur mainly through the Krebs cycle. Alterations in the hexokinase, citrate synthase, glucose-6-phosphate dehydrogenase and glutaminase activities in lymphocytes from patients with Graves' disease, either untreated or on methimazole (MMI) therapy were investigated. Experiments were also done in vitro to determine the activities of these enzymes in normal lymphocytes cultured for 24 h in the presence of MMI T3 and T4 using concentrations close to the physiological. Changes in the conversion of [U-14C]-glucose and [U-14C]-glutamine to 14CO2 as caused by the addition of MMI, T3 or T4 to the culture medium were also evaluated. The results indicate that high levels of thyroid hormones might stimulate the metabolism of glucose and glutamine for a short period of time but, if the stimulus is maintained, the utilization of glutamine by lymphocytes is then suppressed. Moreover, MMI does affect lymphocyte metabolism but the significance of this finding for its immunosuppressive effect remains to be examined.

This study examined the effect of insulin on rat macrophage metabolism and function. The following parameters were studied: cell migration in response to thioglycollate and BCG stimuli, macrophage phagocytic capacity, H2O2 production, glucose and glutamine metabolism as indicated by the measurement of enzyme activities, the utilization of metabolites and production and oxidation of substrates. The results indicate that insulin: (1) did not affect cell migration in response to thioglycollate and BCG; (2) enhanced the phagocytic capacity of macrophages and the production of H2O2 by macrophages; (3) increased the metabolism of glucose and reduced that of glutaminase.