Nucleoside-nucleotide mixture increases bone marrow cell number and small intestinal RNA content in protein-deficient mice after an acute bacterial infection.

The aim of this study was to determine if intraperitoneal administration of a nucleoside-nucleotide mixture would affect small intestinal morphology, bone marrow cell number, and DNA content in protein-deficient mice subjected to acute bacterial infection. Mice were randomized into two groups and orally fed protein-free diet or nucleotide-free 20% casein diet for 10 d. The mice in each group were divided into two subgroups and intraperitoneally administered 0.35 mL saline or nucleoside-nucleotide mixture (17.5 mL/kg body weight) for 10 d. On day 10, one subgroup from each major dietary group was either inoculated intravenously with methicillin-resistant Staphylococcus aureus or saline. Three days later, small intestinal morphology, bone marrow cell number, and DNA content were evaluated in infected and noninfected mice. Protein-deficiency in association with infection significantly (P < 0.05) reduced body weight, small intestinal weight, crypt depth, villous height, and wall thickness. All dietary groups exhibited similar small intestinal DNA and protein contents (protein:DNA ratio, RNA:DNA ratio) at 3 d postinfection. However, small intestinal RNA content in the infected protein-free dietary group administered nucleoside-nucleotide mixture was higher (P < 0.05) and tended to be higher relative to the infected nucleotide-free 20% casein group administered nucleoside-nucleotide mixture compared with the rest of the groups. In the infected protein-free dietary group administered nucleoside-nucleotide mixture, bone marrow cell number and bone marrow DNA content were higher (P < 0.05) relative to the infected protein-free dietary group, nucleotide-free 20% casein diet administered saline, or nucleoside-nucleotide mixture, respectively. We conclude that intraperitoneal administration of nucleoside-nucleotide mixture may stimulate bone marrow cell proliferation, DNA content, and small intestinal RNA content during periods of relative deficiency such as protein-deficiency in combination with infection.

Prophylactic effect of dietary glutamine supplementation on interleukin 8 and tumour necrosis factor alpha production in trinitrobenzene sulphonic acid induced colitis.

BACKGROUND: It is well established that glutamine supplemented elemental diets result in less severe intestinal damage in experimental colitis. However, few studies have examined the mode of action of glutamine in reducing intestinal damage. AIMS: To examine the effects of glutamine supplemented elemental diets on the potent inflammatory cytokines interleukin 8 (IL-8) and tumour necrosis factor alpha (TNF-alpha) in trinitrobenzene sulphonic acid (TNBS) induced colitis which presents with both acute and chronic features of ulcerative colitis. METHODS: Sprague-Dawley rats were randomised into three dietary groups and fed 20% casein (controls), or 20% casein supplemented with either 2% glutamine (2% Gln) or 4% glutamine (4% Gln). After two weeks they received intracolonic TNBS to induce colitis. RESULTS: Both Gln groups of rats gained more weight than the control group (p < 0.05) which had progressive weight loss. Colon weight, macroscopic, and microscopic damage scores for the Gln groups were lower than in the control group (p < 0.05). IL-8 and TNF-alpha concentrations in inflamed colonic tissues were lower in the Gln groups than in the control group (p < 0.05), and correlated well with disease severity. Bacterial translocation was lower both in incidence (p < 0.05) and in the number of colony forming units (p < 0.05) for the Gln groups, than in the control group. With respect to all indices studied, the 4% Gln group performed better than did the 2% Gln group. CONCLUSION: Prophylactic glutamine supplementation modulates the inflammatory activities of IL-8 and TNF-alpha in TNBS induced colitis.

Nucleoside-nucleotide-free diet suppresses cytokine production and contact sensitivity responses in rats with trinitrobenzene sulphonic acid-induced colitis.

We examined the effects of dietary nucleoside-nucleotide mixture on synthesis of inflammatory cytokines, interleukin-8 and tumor necrosis factor-alpha, in sensitized and nonsensitized colitic rats. Sensitized and nonsensitized colitic rats that were fed a nucleoside-nucleotide mixture had greater colonic weight and macroscopic and microscopic damage scores than nucleoside-nucleotide-free sensitized and nonsensitized colitic rats. Increased colonic tumor necrosis factor-alpha and interleukin-8 concentrations were associated with increased colonic inflammation and ulceration in the nucleoside-nucleotide mixture-fed group. There was also increased ear thickness in the nucleoside-nucleotide mixture-fed sensitized and nonsensitized colitic rats, which correlated highly with increased tumor necrosis factor-alpha and interleukin-8 levels in the ear lobes. Nucleoside-nucleotide-free diets may suppress cytokine secretion, thereby reducing colonic damage and contact sensitivity responses in colitic rats.

Modulation of age-related changes in immune functions of protein-deficient senescence-accelerated mice by dietary nucleoside-nucleotide mixture supplementation.

In the present study we examined the immune-enhancing effect of a nucleoside-nucleotide mixture on the non-specific T-cell immune functions of senescence-accelerated mice (SAM) fed on a low-protein diet. The immune functions studied were in vitro thymic and splenic cell lymphoproliferative responses to phytohaemagglutinin, lipopolysaccharide and concanavalin A and their production of interleukin-2 (IL-2) and interferon-gamma (INF-gamma) in response to mitogen stimulation. SAMP8 mice aged 3 and 6 months were used. In each age group, mice were fed on diets containing either 50 g casein/kg, 50 g casein/kg supplemented with 5 g nucleoside-nucleotide mixture/kg or 200 g casein/kg for 3 weeks. The supplemented 3- and 6-month-old mice had higher (P < 0.05) thymic and splenic cell counts compared with the low-protein group. In both age groups of mice, concanavalin A induced higher (P < 0.05) total thymic and splenic lymphoproliferative responses for the nucleoside-nucleotide mixture-supplemented group compared with the 50 g casein/kg dietary groups. Thymic and splenic production of IL-2 was higher for the 3-month-old mice in both the supplemented and the 200 g casein/kg dietary groups. INF-gamma production in the supplemented 3-month-old group and the 6-month-old 200 g casein/kg dietary group was higher (P < 0.05) compared with the other groups. Overall the supplemented 3-month-old mice exhibited both higher lymphoproliferative responses and production of cytokines compared with the supplemented 6-month-old mice. The results indicate that early nucleoside-nucleotide mixture supplementation may enhance the immune response in protein-deprived SAMP8 mice.

Role of nucleosides and nucleotides in the immune system, gut reparation after injury, and brain function.

Emerging evidence indicates the importance of nucleosides and nucleotides in the maintenance of functions of the bone marrow hematopoietic cells, intestinal mucosa, and the brain, which have limited de novo synthesis of purine and pyrimidine bases. We have found that nucleosides and nucleotides stimulate hemopoieses and increase peripheral neutrophil counts in mice treated with cyclophosphoamide. Intraperitoneal administration of nucleosides and nucleotides decreased bacterial translocation, the number of colony-forming units, and increased survival against methicillin-resistant Staphylococcus aureus. In vitro immune studies in mice showed that nucleosides and nucleotides increase the delayed-type cutaneous hypersensitivity and the popliteal lymph node blastogenic response to antigens, allogens, and mitogens. Both intraperitoneal and oral administration of nucleosides and nucleotides reduced endotoxin-induced bacterial translocation and improved injury to the gut in protein-deficient mice. However, oral administration of nucleosides and nucleotides in experimental colitis resulted in a worsening of colitic conditions and increased interleukin-8 and tumor necrosis factor-alpha concentrations in inflamed colonic portions, indicating the pro-inflammatory activities of nucleosides and nucleotides. Memory-deficient senescence-accelerated mice and mice with dementia showed improved memory with dietary nucleosides and nucleotides supplementation. These results indicate that supplementation with nucleosides and nucleotides is beneficial to the functions of the system and the brain. However, beneficial effects to the gut appear to depend on the type of damage sustained by the gut.

Nucleoside-nucleotide free diet protects rat colonic mucosa from damage induced by trinitrobenzene sulphonic acid.

BACKGROUND: Growing evidence suggests that intestinal recovery from injury induced by radiation, endotoxin, and protein deficiency is improved by the ingestion of nucleosides and nucleotides. AIM: This study examined the effect of dietary nucleosides and nucleotides supplementation on trinitrobenzene sulphonic acid induced colonic damage in experimental colitis. METHODS: Sprague-Dawley rats were randomised into two groups and fed nucleic acid free 20% casein diet (control) or this diet supplemented with 0.5% nucleoside-nucleotide mixture for four weeks. On the second week, colonic inflammation was induced in rats by intracolonic administration of 0.25 ml of 50% ethanol containing 25 mg of trinitrobenzene sulphonic acid. Additionally, other sets of rats were treated with 0.25 ml of 50% ethanol, 25 mg of trinitrobenzene sulphonic acid in 0.25 ml saline, or 0.25 ml of 0.9% saline. RESULTS: After two weeks, colon weight, macroscopic and microscopic damage scores, were significantly greater (p < 0.05) in the nucleoside-nucleotide supplemented group compared with the non-supplemented control groups. The same variables seen in the trinitrobenzene sulphonic acid-ethanol group fed nucleoside-nucleotide free diet were greater (p < 0.05) than in the rest of the groups fed nucleoside-nucleotide free diet and treated with ethanol, trinitrobenzene sulphonic acid in saline, or saline. Histologically, segmental ulceration and inflammation associated with significantly increased infiltration of polymorphonuclear leucocytes, macrophages, lymphocytes, fibroblasts were observed in the supplemented group compared with the controls. In the nucleoside-nucleotide supplemented group the epithelial damage, mucosal erosion, oedema, and coagulative necrosis of the muscularis propria was more extensive in comparison to the non-supplemented control groups. CONCLUSIONS: This study suggests that dietary nucleosides and nucleotides may aggravate colonic damage and inflammation in chemically induced experimental colitis in rats; and that nucleoside-nucleotide free diet combined with other pharmacological agents may offer a better response.

A nucleoside-nucleotide mixture and its components increase lymphoproliferative and delayed hypersensitivity responses in mice.

We studied the effect of individual components of a nucleoside-nucleotide mixture on T cell-mediated immunity in BALB/c and DBA/2 mice. Mice were fed for 4 wk a nucleotide-free 20% casein diet (control) or this diet supplemented with 3 mol/kg of one of the following; inosine, guanosine monophosphate, uridine, cytidine, thymidine, or a mixture of these. In both strains of mice, popliteal lymph node immunoproliferative response to alloantigeneic (C57BL/6 splenic cells) challenge in mice fed the mixture and guanosine monophosphate was greater (P < 0.05) than in the mice fed the control diet. BALB/c mice fed inosine, uridine, and thymidine also showed greater (P < 0.05) responses compared with control fed mice. In the sheep red blood cells challenge assay, foot pad weight-gain in both strains of mice fed the mixture and the individual components supplemented diets was greater (P < 0.05) than in those fed the control diet. In both strains of mice, interleukin-2 secretion by popliteal lymph node lymphocytes in mice fed the mixture and thymidine was higher (P < 0.05) compared with the rest of the groups except BALB/c mice fed cytidine. Significantly higher than control secretions of interferon-gamma were observed only in BALB/c mice fed inosine, thymidine and the mixture. We conclude that mice fed the nucleoside-nucleotide mixture and the individual components of the mixture had greater responses in the T cell-mediated immune functions studied and that the responses in mice fed the mixture were not different from those in mice fed the individual components.