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Arginine-containing compounds and thymic endocrine activity
Abstract
The frequent association of malnutrition, infectious disease and aging has stressed the role played by some nutrients on the immune efficiency and particularly on the age-dependent immunological decline. Since arginine has been proven to enhance immune efficiency as demonstrated by the observation that supplemental dietary arginine accelerates would healing and increases thymus weight, we have evaluated the influence of oral administration of arginine on the age-associated immune deficiencies and in particular on the reduced thymic endocrine activity, as measured by the circulating level of one of the best known thymic peptides, i.e. thymulin. Thirty days oral treatment with arginine at the dose of 0.03 g/Kg b.w./day in 20 month old mice induces a full recovery of thymic endocrine activity and a significant increase of PHA responsiveness by spleen cells, when compared with untreated age-matched controls. In humans, oral administration of a commercially available arginine-lysin combination (Lysargin, Baldacci, Pisa, Italia) at the dose of 4 gr. of arg. + 4 gr. of Lysine induces a significant increment of thymulin blood level both in elderly and in cancer patients and at peripheral level, an increase of CD4+ lymphocyte subpopulation. These findings confirm the immunomodulation role of arginine and suggest that on the target of arginine as the thymus and particularly its endocrine activity. Furthermore arginine and arginine-containing compounds may offer a new therapeutical approach to restore thymic immunodeficiencies associated with age or secondary to pathologies inducing thymic deterioration such as trauma, stress and cancer.
... The second line of evidence is the thymus re-growth induced in old age by some endocrinological manipulations and/or nutritional interventions as following: a) the intrathymic transplantation of the pineal gland or treatment with melatonin [46], b) the implantation of growth hormone secreting tumour cell lines (GH3 cells) [47] or treatment with exogenous GH [48,49], c) castration [50], d) treatment with exogenous LH-RH [51], e) treatment with exogenous thyroxine (T 4 ) [52], f) nutritional intervention with arginine [53], g) nutritional intervention with zinc supplementation [45,54]. These findings suggest an influence of hormones and nutritional factors on thymic functions. ...
... b.w./day) for 20 days increases plasma levels of thymulin when compared to saline treated animals. The effect is directly exerted on the thymus because the transplantation of the thymus gland from old arginine treated mice into young-thymectomized recipients restores plasma levels of thymulin [53]. A restoration of NK cell cytotoxicity also occurs in old mice treated with arginine with even more significant increments in boosted IFN-γ/NK cell cytotoxicity [13]. ...
The restoration of the thymic functions and the thymic re-growth may be achieved in old mice by some endocrinological (melatonin) or nutritional interventions (arginine or zinc), suggesting that the thymic involution in old age is a phenomenon secondary to age-related alterations occurring in neuroendocrine-thymus interactions. The targets for the thymic restoration may be hormone receptors and cytokines, strictly related to the presence of two nutritional factors, such as arginine and zinc, which are in turn essential for the efficiency of neuroendocrine-immune network both in ontogeny and ageing. The effect of melatonin is largely due to the presence of its specific receptors on cell membrane of thymocytes and Thymic Epithelial Cells (TECs). TECs synthesize thymulin peptide that is required for T-cell differentiation and maturation within the thymus gland. In this context, the role of zinc is pivotal because it is involved, through "zinc finger motifs", in the gene expression of melatonin receptors, in cell proliferation, apoptosis and thymulin reactivation. Zinc is also required for the biological action of arginine, via Nitric Oxide pathway. Therefore, the beneficial effect of melatonin or arginine on neuroendocrine-thymus interaction in ageing can also occur via a better zinc pool redistribution within the body where the capability of the zinc-binding proteins Metallothioneins (MT) in zinc release has a key role. These findings suggest that zinc, via MT buffering, can be a single mediator in modulating neuroendocrine-thymus interaction in ageing.
... Arginine stimulates T-cell responses, thereby reducing the inhibitory effect of injury on T-cell function (Barbul et al., 1980a, b;Fabris and Mocchegiani, 1992). T lymphocytes are essential for normal wound healing as evidenced by decreased wound breaking strength in animals treated with monoclonal antibodies against T lymphocytes (Peterson et al., 1987). ...
Arginine is a conditionally essential amino acid that plays a number of critical roles in human health and disease. Since discovering arginine to be the nitrogen source for nitric oxide, biomedical research has intensely focused on it and its vasodilatory effects. However, other recent work has highlighted not only these potential cardiovascular benefits of arginine and its metabolites but also the advances in the knowledge of arginine biochemistry, organ–organ trafficking, and insights from clinical studies examining its role of arginine as a therapeutic modality in a variety of disease states. These advances, along with a comprehensive review of arginine biochemistry and physiology, are reviewed within this chapter and aim to highlight this robust area of medical research.
... Then the hypothalamus stimulates vagal afferent and sympathetic nerve system to thymus gland, spleen and lymph nodes. The thymus gland after stimulated by the sympathetic and vagal efferent nerves will increase the release of T lymphocytes, including T helper cells, so CD4 counts will increase [15,16]. Lysine can also increase absorption of zinc. ...
Elderly people tend to have higher susceptibility of infections because immune dysfunction, especially cell-mediated immune system which is related to zinc deficiency. Lysine can support zinc role to boost up the cell-mediated immune system which can be determined by CD4 count. The objective of this study is to determine the effect of zinc and lysine supplementation on infection rate and CD4 count in elderly.
A randomized, double-blind, placebo-controlled trial was conducted in a senior center in Surabaya using 24 healthy elderly subjects of both sexes aged 62 to 90 years. They were divided into two experimental groups and one control group. They were given zinc 20 mg per day; or zinc 20 mg and lysine 500 mg per day; or placebo for 2 months. Infection rate during supplementation period was documented. Albumin level, serum zinc level and CD4 count were measured before and after supplementation. The data was analyzed using one way Anova and paired T-test with p < 0.05.
Compared to control group, infection rate was lower in zinc group and zinc + lysine group (p < 0.065). Zinc + lysine supplementation increased serum zinc level significantly (p < 0,012) and had better effect compared to zinc supplementation alone. Zinc + lysine supplementation also increased CD4 count (p < 0,784) and had better effect compared to zinc supplementation alone. Zinc + lysine supplementation did not increase albumin level which was already in the normal level. Zinc + lysine supplementation can reduce infection rate in elderly by increasing zinc level and CD4 count.
... injections every 3 days for 1 month. l-Arg was supplemented in drinking water at the dose of 1.4 × 10 −3 g/die for 1 month (Fabris and Mocchegiani, 1992; Mocchegiani et al., 1994; Schäfer et al., 2005). Mice were divided in three groups of n. 8 animals/group: control group (Ctrl), Hg group (Hg), Hg plus l-Arg group (Hg + Arg). ...
... injections every 3 days for 1 month. l-Arg was supplemented in drinking water at the dose of 1.4 × 10 −3 g/die for 1 month (Fabris and Mocchegiani, 1992; Mocchegiani et al., 1994; Schäfer et al., 2005). Mice were divided in three groups of n. 8 animals/group: control group (Ctrl), Hg group (Hg), Hg plus l-Arg group (Hg + Arg). ...
Inorganic mercury (HgCl2) exposure provokes damage in many organs, especially kidney. Inducible nitric oxide synthase (iNOS) expression, total NOS activity and the profiles of zinc (Zn), copper (Cu) and Hg as well as their distribution when bound to specific intracellular proteins, including metallothioneins (MT), were studied during HgCl2 exposure and after l-arginine treatment in C57BL/6 mouse kidney. HgCl2 exposure modulates differently iNOS expression and NOS activity, increasing iNOS expression but, conversely, decreasing total NOS activity in the mouse kidney. Moreover, during Hg exposure an increased MT production occurs. The kidney damage leads to a loss of urinary proteins, increased plasma creatinine and high Zn mobilization with consequent increased urinary Zn excretion. l-arginine treatment recovers NOS activity and induces a normalization of MT induction, plasma creatinine values and urinary proteins excretion, suggesting that l-arginine may limit kidney damages by Hg exposure.
... It has generally been understood that the endogenous rate of arginine synthesis can satisfy the physiological de mands of adult organisms, but not the demands of growing organs or organisms requiring active and rapid cell proliferation and activity. Although the evi dence is very fragmentary, there is evidence that ar ginine can have an effect on the immune system, particularly the endocrine activity of the thymus (Fabris and Mocchegiani 1992). ...
The objective of these experiments in pigs were to test the hypotheses that 1) gut synthetic processes could adapt to additional dietary glutamate or ornithine to meet tissue needs for arginine with feeding arginine-deficient diets and 2) acute elevation of ammonium in the hepatic-portal blood leads to increased glutamine production. Arterial [117 +/- 5.3 (arginine-deficient) vs. 78 +/- 5 (arginine-adequate) mumol/L] and portal ammonium concentrations were elevated in pigs fed arginine-deficient diets. Dietary ornithine, which elevated portal-drained visceral flux of ornithine, corrected the urinary orotic aciduria, but not the hyperammonemia seen with feeding arginine-deficient diets. Concentrations or portal drained viscera fluxes of arginine, ornithine, glutamate and glutamine were not altered even though portal and arterial ammonium concentrations were increased 8- and 3.5-fold with mesenteric infusion of ammonium. It was concluded that 1) substitution of glutamate for glycine or alanine does not alter gut production of ornithine, citrulline or arginine; 2) gut citrulline production is not altered by levels of dietary arginine, ornithine or glutamate; 3) increased ammonium challenge does not lead to increased glutamine production even though peripheral ammonium levels increased over threefold; and 4) provision of arginine for tissue needs will have to be met from dietary sources, as adaptations in gut synthetic processes seem to be refractory to dietary arginine status.
... Thus, the mechanisms that relate spermidine levels to arginine intake in each organ and their physiologic relevance remain to be analyzed. We hypothesize that the positive correlation between spermidine levels and arginine intake in thymus could be related to the effect of arginine in improving its endocrine activity (8,65). Another aspect that merits further investigation is the importance of the changes in polyamines in adipose tissue on fat accumulation and obesity (9,66). ...
Many key metabolic and physiologic functions involve arginine and arginine-derived metabolites. Requirements for arginine, a "conditionally essential" amino acid for most mammalian species, are met in variable proportions by dietary intake and endogenous synthesis, the latter being sufficient to fulfill arginine needs in adult humans and mice under nonpathologic conditions. However, dietary arginine restriction causes orotic aciduria and abnormal function of the urea cycle. Furthermore, the importance of dietary arginine in the maintenance of homeostasis of arginine-derived metabolites in the body has not yet been analyzed in detail. We therefore examined whether the deprivation or supplementation of dietary arginine affects tissue and circulating levels of arginine-derived polyamines. We pair-fed male Swiss albino mice (30 g) for 15 or 30 d synthetic diets containing 0, 1.12 or 2.24 g/100 g L-arginine. Tissue and blood levels of the main free polyamines, putrescine, spermidine and spermine, were measured by HPLC. In general, neither the deprivation nor the supplementation of arginine dramatically affected the levels of any of the polyamines analyzed. Variations were organ, time and polyamine specific, and most differences were in the levels of putrescine at 15 d and of spermidine at 30 d. Thus, in contrast to effects on urea cycle function, dietary arginine does not appear to be essential for the maintenance of the homeostasis of free polyamine levels in adult mice, emphasizing the importance of endogenous arginine synthesis in preserving the polyamine body pool.
... Albina et al. (1989a,b) reported that L-arginine in culture media enhanced functions in rat peritoneal macrophages including cytotoxicity against tumor cell superoxide production and phagocytosis. Fabris and Mochegiani (1992) have evaluated the influence of oral administration of arginine on the age-associated immune deficiencies, since arginine has been proven to enhance immune efficiency as demonstrated by the observation that supplemental dietary arginine accelerates wound healing and increases thymus weight. It has been demonstrated that arginine supplementation enhanced in vitro lymphocyte proliferation in healthy adult humans and in rodent models (Lewis and Langkamp-Henken, 2000). ...
Aging is associated with decline in the functioning of immune cells and reductions in serum L-arginine and excretion of nitric oxide metabolites. Studies have shown that L-arginine plays an important role in many physiological, biological and immunological processes. The present study was performed to determine if treatment with L-arginine could prevent age-related changes in phagocytic function of peritoneal macrophages. The effects of L-arginine on phagocytic activity of peritoneal macrophages were compared between young and middle-aged rats. Studies were performed in four groups of rats for 8 weeks: group 1 (3 month-old) received physiological saline; group 2 (3 month-old) received L-arginine (160 mg/kg/day); group 3 (12 month-old) received physiological saline; group 4 (12 month-old) received L-arginine (160 mg/kg/day). There were no significant differences in percentage of cells which were phagocytized. However, the phagocytosis of activated charcoal by peritoneal macrophages reduced with age. Thus, the phagocytic index was lower in macrophages of middle-aged rats. L-arginine treatment increased phagocytosis by peritoneal macrophages of both young and middle-aged rats. L-arginine-induced augmentation in phagocytosis by macrophages were much higher in the middle-aged rats compared with young rats. In summary, we found that L-arginine prevented the age-related reduction in phagocytic capability of peritoneal macrophages.
... Alternatively, other antioxidants may be used, especially those related to the zinc pool. Arginine may be useful because its action, other than as substrate for NO production, is exerted by means of the zinc pool (Fabris and Mocchegiani, 1992) and thus may enhance endogenous zinc ion availability avoiding the addition of exogenous zinc, which can be harmful in AD. It is important to remember that zinc supplementation is particularly useful in preserving good health in the presence of marginal zinc deficiency, which is a common event in the elderly (Vaquero, 2002). ...
Actual fields of research in neurobiology are not only aimed at understanding the different aspects of brain aging but also at developing strategies useful to preserve brain compensatory capacity and to prevent the onset of neurodegenerative diseases. Consistent with this trend much attention has been addressed to zinc metabolism. In fact, zinc acts as a neuromodulator at excitatory synapses and has a considerable role in the stress response and in the functionality of zinc-dependent enzymes contributing to maintaining brain compensatory capacity. In particular, the mechanisms that modulate the free zinc pool are pivotal for safeguarding brain health and performance. Alterations in zinc homeostasis have been reported in Parkinson's and Alzheimer's disease as well as in transient forebrain ischemia, seizures and traumatic brain injury, but little is known regarding aged brain. There is much evidence that that age-related changes, frequently associated to a decline in brain functions and impaired cognitive performances, could be related to dysfunctions affecting the intracellular zinc ion availability. A general agreement emerges from studies of humans' and rodents' old brains about an increased expression of metallothionein (MT) isoforms I and II, but dyshomogenous results are reported for MT-III, and it is still uncertain whether these proteins maintain in aging the protective role, as it occurs in adult/young age. At the same time, there is considerable evidence that amyloid-beta deposition in Alzheimer's disease is induced by zinc, but the pathological significance and the causes of this phenomenon are still an open question. The scientific debate on the role of zinc and of some zinc-binding proteins in aging and neurodegenerative disorders, as well as on the beneficial effect of zinc supplementation in aged brain and neurodegeneration, is extensively discussed in this review.
... Taking into account that arginine has a secretagogue action on GH, which in turn has an immuno-modulatory action (Fabris et al., 1997), one of the mechanism of arginine on immune responses may be related to GH. The best evidence in supporting this mechanism is the observation that the enhancing effect of arginine on allograft rejection, on resistance of rats to viral tumours and on recovery of thymus weight after injury were all abrogated by previous hypophysectomy and restored by GH (Reynolds et al., 1990;Fabris and Mocchegiani, 1992). This would clearly suggest that an intact pituitary-thymus axis is required for arginine action. ...
Thymic re-growth and reactivation of thymic functions may be achieved in old animals by different endocrinological or nutritional manipulations such as, (a) treatment with melatonin, (b) implantation of a growth hormone (GH) secreting tumour cell line (GH3 cells) or treatment with exogenous GH, (c) castration or treatment with exogenous luteinizing hormone-releasing hormone (LHRH), (d) treatment with exogenous thyroxin or triiodothyronine, and (e) nutritional interventions such as arginine or zinc supplementation. These data strongly suggest that thymic involution is a phenomenon secondary to age-related alterations in neuroendocrine-thymus interactions and that it is the disruption of these interactions in old age that is responsible for age-associated immune-neuroendocrine dysfunctions. The targets involved in hormones-induced thymic reconstitution may directly or indirectly involve hormone receptors, cytokines, arginine, and a trace element such as zinc, which is pivotal for the efficiency of neuroendocrine-immune network during the whole life of an organism. The effect of GH, thyroid hormones, and LHRH may be due to specific hormone receptors on thymocytes and on thymic epithelial cells (TECs), which synthesize thymic peptides. Melatonin may also act through specific receptors on T-cells. In this context, the role of zinc, which turnover is reduced in old age, is pivotal because of its involvement through zinc fingers in the gene expression of hormone receptors. In addition, the effects of zinc are multifaceted: from the reactivation of zinc-dependent enzymes, to cell proliferation and apoptosis, to cytokines expression and to the reactivation of thymulin, which is a zinc-dependent thymic hormone required for intrathymic T-cell differentiation and maturation as well as for the homing of stem cells into the thymus. Zinc is also required for arginine action, via NO pathway. The role of zinc is therefore crucial in neuroendocrine-thymus interactions. According to data in animals and humans, the above reported endocrinological manipulations (GH, thyroid hormones, and melatonin) or arginine treatment may also act via zinc pool in restoring thymic activity in ageing allowing improvements on peripheral immune efficiency.
In vivo treatment with parenterally administered hypoxanthine
derivatives, notably ST 789, was able to protect cyclophosphamide-immunosuppressed mice against
experimental infections with both bacterial and fungal pathogens. However, the mechanisms accounting
for these effects of hypoxanthine derivatives remain to be fully established. In fact, only the treatment with
ST 789 resulted in a clear enhancement of the primary antibody production as well as macrophage
phagocytic activity, whereas T lymphocyte responsiveness to mitogens and both macrophage- and natural
killer-dependent cytotoxicity were not significantly affected. These data, together with the recently shown
ability of ST 789 to increase interleukin-6 production, suggest that monocyte/macrophages are likely to be the main cellular target of the immunomodulating activity of ST 789. Finally, in the presentln vivo study, hypoxanthine derivatives did not enhance the mean survival time of tumour-bearing immunosuppressed mice.
Thymic re-growth and reactivation of thymic functions may be achieved in old animals by different endocrinological or nutritional manipulations such as, (a) treatment with melatonin, (b) implantation of a growth hormone (GH) secreting tumour cell line (GH3 cells) or treatment with exogeneous GH, (c) castration or treatment with exogenous luteinizing hormone-releasing hormone [LHRH], (d) treatment with exogenous thyroxin or triiodothyronine, and (e) nutritional interventions such as arginine or zinc supplementation. These data strongly suggest that thymic involution is a phenomenon secondary to age-related alterations in neuroendocrine-thymus interactions and that it is the disruption of these interactions in old age that is responsible for age-associated immune-neuroendocrine dysfunctions. The mechanisms involved in hormone-induced thymic reconstitution may be direct or indirect involving hormone receptors, cytokines and a trace element such as zinc, which is pivotal for the efficiency of neuroendocrine-immune network during the life-span of an organism. The effect of GH, thyroid hormones, and LHRH are due to specific hormone receptors on thymocytes and on thymic epithelial cells (TECs), which synthesize thymic peptides. Melatonin may also act through specific receptors on T-cells. In this context, the role of zinc, whose turnover is reduced in old age, is fundamental because of its involvement in zinc finger proteins that regulate gene expression for hormone receptors. However, the effects of zinc are multifaceted: it spans from the reactivation of zinc-dependent enzymes, to cell proliferation and apoptosis, to cytokines expression and to the reactivation of thymulin, which is a zinc-dependent thymic hormone required for intrathymic T-cell differentiation and maturation as well as for the homing of stem cells into the thymus. Therefore, the role of zinc is crucial in neuroendocrine-thymus interactions. According to current experimental data in animals and humans, the endocrinological manipulations for the maintenance of thymus function [e.g. by GH, thyroid hormones or melatonin] act via the zinc pool in restoring thymic activity and improving adaptive immunocompetence in ageing.
The thymus and in particular its epithelial component produces hormonal peptides which are required for differentiation of stem cells into mature T-cells. With advancing age, there occurs a progressive reduction of the plasma level of one of the best known thymic peptides, i.e. thymulin. In old mice, oral supplementation with arginine (9x10(-4) gr/day/mouse) for 1 month is able to induce a regrowth of the thymus and recovery of the reduced thymulin plasma level to the values observed in young animals. The direct immunological target of arginine seems to be the thymus gland. In fact, the transplantation of thymus from old arginine treated mice into young thymectomized recipients is able to restore thymulin plasma level in thymectomized recipients to nearly the same level as do thymuses from young mice. Furthermore, arginine supplementation young thymectomized recipients is unable to induce the reappearance of thymulin activity in the blood. With regard to the mechanism of action of arginine, two pathways may be suggested. The first one may be indirect and mediated by the secretagogue action of arginine on growth hormone. The second one, may rely on a direct action through the L-arginine: NO pathway. Lymphocyte-depleted thymic explants from young mice, when incubated in vitro with the NO-synthetase inhibitor L-NAME (6 mM), are, in fact, incapable of producing and realising thymulin in the supernatant. The in vitro addition of L-arg (60 mM) is able to recover such a production to the values observed in supernatants of control thymic cultures. The present findings offer the first evidence that also the thymic endocrine activity is modulated by L-arginine:NO pathway.
Previous work from this laboratory has demonstrated that both a trace element, zinc, and an amino acid, arginine, are capable, when orally administered, to recover some age-related immune dysfunctions. In the present paper the effectiveness of a zinc-arginine combination versus the single nutrients in restoring age-related immunological alterations in old Balb/c mice has been investigated. The zinc-arginine combination is more effective than the treatments of single nutrients alone. In particular on the reactivation of thymic endocrine activity, as measured by the circulating level of one of the best known thymic factors, i.e. thymulin (Zn-FTS) and the natural killer (NK) cell activity, particularly under boosting condition by interleukin-2 (IL-2) or interferon (IFN). On the other parameters tested the zinc-arginine combination either was not more effective than the single nutrients or a prevalence of one of them was detectable, such as of arginine on mitogen response or of zinc on basal NK activity. The findings clearly suggest that nutritional interventions and particularly combination of nutrients may represent an interesting and side-effect deprived approach for immunorestoration in elderly people.
Nitric oxide (NO) play a pivotal role in many biological processes, as in the vessel tone control, the atherogenesis, the platelets aggregation and the immune system modulation. The physiologic precursor of NO is the L-arginine. Evidence exists that the L-arginine administration can stimulate immune system in children with recurrent infections. This clinical trial was designed to evaluate the effects of oral administration of L-arginine on the number of infective events and on the lymphocytes subsets in children suffering from airways recurrent infections.
Forty outpatients, 21 male and 19 female, aging from 2 to 13 yrs. Two balanced groups, treated for 60 days with L-arginine or a placebo. Evaluation criteria: number of septic episodes; number of circulating white blood cells, % of the lymphocytes; lymphocytes subsets.
Descriptive analysis; inference tests: chi 2; "t" test; variance analysis. Statistical significance: p = 0.05.
Fifteen patients treated with L-arginine and five treated with placebo (p < 0.01) were free from infections. The percentage of CD3 and CD4 subsets significantly (p < 0.05) increased in the L-arginine group than in the placebo group, while the CD8 subset significantly decreased. The CD4/CD8 ratio raised from 1.05 +/- 0.29 to 1.51 +/- 0.46 (p < 0.01) in the L-arginine group, from 1.12 +/- 0.16 to 1.27 +/- 0.24 in the placebo group. There were no side effects in both groups.
L-arginine seems able to increase the immune system defences and to protect against the airway infections.
Orally applied non-digestible carbohydrates (NDC) have been associated with immune-modulating effects and other health benefits. The effects of prebiotic carbohydrates have recently received much attention, but other NDCs have been reported to induce immune modulation as well. Many different effects have been shown on parameters of innate and specific immunity, mostly in animal experiments or in vitro. Data from clinical trials are limited, but promising studies have reported beneficial effects on mucosal and systemic immunity in humans. NDCs are fermented to various degrees by the intestinal microbiota. Therefore, immune-modulatory properties have often been attributed to microbiota-dependent effects, especially in the case of prebiotic NDCs. However, some NDCs have been reported to bind to specific receptors on cells of the immune system, suggesting microbiota-independent, immune-modulatory effects play a role as well. This review aims to provide an overview of the published immune-modulatory effects in vitro and in vivo induced by NDCs such as fructans, galactooligosaccharides, β-glucans, pectins, and resistant starch. In addition, issues related to the underlying mechanisms are discussed: interaction between bacteria, their metabolites and the immune system, as well as direct effects of NDCs via lectin receptors.
Nitric oxide (NO) has become recognized as a multifunctional mediator, with roles in vascular physiology, neurotransmission and non-specific immune defense. The histochemical marker associated with the neural and endothelial form of NO synthase (NOS), reduced nicotinamide adenine dinucleotide diaphorase (NADPHd), has enabled the indirect localization of potential sites of NO production. Innervation of the thymus and its immunological functions made this tissue a candidate for utilization of various NO systems. In the present study on adult rat thymus, multiple cellular sites expressing NADPHd activity, thereby implicated as sites of NOS activity, have been identified using morphological criteria alone: blood vessel endothelium, dendritic cells, deep cortical or medullary stromal cells, intrinsic neuron-like profiles, granulocytes (possibly neutrophils) and fat cells. In addition, the availability to the thymic microenvironment of another form of NOS in macrophages, which is not stained by the diaphorase technique, was supported by the observation of these cells at corticomedullary and cortical locations. These results indicate that a wide variety of possible immunomodulatory roles can be expected for NO in the thymus including the induction of tolerance, major histocompatibility complex (MHC) restriction, lymphocyte trafficking and regulation of thymic endocrine output.
to evaluate whether oral supplementation with zinc or zinc/arginine increases the antibody response to influenza vaccine or modulates the lymphocyte phenotype in elderly subjects.
a randomized controlled trial with two supplemented groups and one control group.
a community nursing home.
384 subjects aged 64-100 (mean age 82 years) examined in three separate studies.
oral supplementation with zinc (400 mg/day) or zinc plus arginine (4 g/day) for 60 days starting 15 days before influenza vaccination. The control groups received vaccine only.
haematological and nutritional indices, antibody titre against influenza viral antigens, lymphocyte phenotype.
supplementation with zinc or zinc plus arginine increased zinc plasma concentrations restoring the age-related impairment in zinc concentrations to values found in younger people. The antibody titre against influenza viral antigens was not increased in zinc or zinc/arginine supplemented groups in comparison with subjects receiving vaccine alone. The number of CD3, CD4 or CD8 lymphocytes was not affected by zinc or zinc/arginine supplementation.
prolonged supplementation with zinc or zinc/arginine restores zinc plasma concentrations but is ineffective in inducing or ameliorating the antibody response after influenza vaccination in elderly subjects.
The amino acid L-arginine (Arg) has been used extensively in dietary and pharmacological products. This study evaluated toxicological and behavioral effects of Arg produced by Ajinomoto Co. (Tokyo, Japan) during a dosing study with male and female Sprague-Dawley rats. The amino acid was incorporated into a standard diet at doses equal to 1.25%, 2.5%, and 5.0% (w/w). A control group of rats received only a standard diet. All diets were administered ad libitum for 13 continuous weeks. To examine recoverability of any potential effects, the administration period was followed by a 5-week-long recovery, during which only a standard diet was provided. In male and female rats in each concentration group, treatment-related changes were not observed for clinical signs, body weights, diet consumption, ophthalmology, gross pathology, organ weight, or histopathology. An elevated level of plasma glucose was detected in some male rats (5.0%, w/w) during the analysis conducted in the fifth week of administration; however, the degree of the change was within the physiological range, and no changes were observed at the end of the administration period. In the same group, an increase in hemoglobin, together with a tendency toward an increase in the red blood cell counts, was found, but the change was considered toxicologically insignificant. The no-observed-adverse-effect level (NOAEL) for Arg was estimated at 5.0% (w/w) for both genders (males, 3.3 +/- 0.1 g/kg/day; females, 3.9 +/- 0.2 g/kg/day).
Specific mixtures of prebiotic oligosaccharides showed immune modulatory effects in previous murine vaccination experiments, suggesting a shift towards T-helper 1 (Th1) immunity. These mixtures consisted of short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS) in a 9:1 ratio (Immunofortis), with or without pectin-derived acidic oligosaccharides (pAOS). To investigate whether these mixtures could suppress Th2-related responses, they were tested in an ovalbumin (OVA)-induced model for experimental allergic asthma in BALB/c mice. Supplementation with two mixtures of scGOS/lcFOS and scGOS/lcFOS/pAOS at approximately 1% (w/w% net oligosaccharides) in the diet, starting two weeks before OVA sensitization and lasting until the end of the experiment, decreased of several parameters of allergic asthma. The OVA-induced airway inflammation and hyperresponsiveness was significantly suppressed by both mixtures. Moreover, OVA-specific IgE titers were decreased by more than 25%, although this effect was not significant. The effects of the oligosaccharide mixture with pAOS appeared to be more pronounced than the effects of the scGOS/lcFOS mixture without pAOS, but a direct comparison between the mixtures was not made. Overall, the results further support the hypothesis that specific mixtures of oligosaccharides modulate the Th1/Th2 balance by enhancing Th1-related and suppressing Th2-related parameters.
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