The effects of moderate exercise on secretory IgA production in mice depends on dietary carbohydrate intake.

Secretory immunoglobulin A (sIgA) is produced from intestinal mucosa and is essential in preventing infection. We analyzed the influence of moderate exercise on intestinal sIgA production and antioxidative function under different carbohydrate nutritional conditions. Thirty-six mice were fed an experimental diet for 10 weeks-a high-carbohydrate (HC) diet, a low-carbohydrate (LC) diet, or a control (C) diet. After 1 week on the experimental diets, mice were divided into sedentary and exercise groups (n = 6/group), where the exercise consisted of treadmill running for 30 min/day at 11 m/min for 6 days/week in 9 consecutive weeks. Intestinal sIgA levels in the exercise groups fed C or LC diets were significantly lower compared with the parallel sedentary groups, or exercise-group mice fed HC diet. Expression of the polymeric immunoglobulin receptor (pIgR) in the small intestine was significantly higher in the exercise group fed a HC diet. Superoxide dismutase activity in the small intestine was higher in the exercise group than in the sedentary group, with no effects resulting from intake carbohydrate levels. Our results indicated that moderate exercise reduced the levels of intestinal sIgA depending on decreasing of carbohydrate intake, which is connected with the expression of pIgR.

Antiobesity Effect of N-Acetylneuraminic Acid by Enhancing Antioxidative Capacity in Mice Fed a High-Fat Diet.

The sialic acid N-acetylneuraminic acid (NANA), an essential factor in bioregulation, is a functional food component that is known to have beneficial health effects, but its antiobesity effect has not been clearly understood. Adipocyte dysfunction in obesity involves a decrease in the level of NANA sialylation. In this study, we investigated the antiobesity effect of NANA in mice fed a high-fat diet (HFD) and in 3T3-L1 adipocytes. Male C57BL/6J mice were randomly divided into three groups and administered the following diets: a normal diet, an HFD, and an HFD with 1% NANA supplementation for 12 weeks. NANA supplementation significantly reduced body weight gain; epididymal adipose tissue hypertrophy; and serum lipid, fasting glucose, and aspartate transaminase levels compared with those in HFD mice. The percentage of lipid droplets in hepatic tissue was also decreased by NANA supplementation in HFD mice. The downregulation of Adipoq expression and upregulation of Fabp4 expression induced by HFD in epididymal adipocytes were improved by NANA supplementation. The downregulation of Sod1 expression and increase in malondialdehyde level were induced by HFD, and they were significantly improved in the liver by NANA supplementation, but not in epididymal adipocytes. However, NANA supplementation had no effect on sialylation and antioxidant enzyme levels in mouse epididymal adipocytes and 3T3-L1 adipocytes. Overall, NANA exerts antiobesity and antihypolipidemic effects and may be beneficial in suppressing obesity-related diseases.

Microglia and astroglia prevent oxidative stress-induced neuronal cell death: implications for aceruloplasminemia.

We partially characterized the transferrin-independent iron uptake (Tf-IU) of neuronal and glial cells in the previous report. In the present study, we further examined a mechanism of which glial cells protect neuronal cells against iron stress using neuron-microglia (N-MG) and neuron-astrocyte (N-AS) co-cultures. When each solely purified cell was treated with iron citrate, cell death occurred in N and MG. However, AS proliferated under the same condition. Both N-MG and N-AS co-cultures were effective in resistance to excessive iron. The total and specific Tf-IU activities of N-MG co-cultures similar to those of N did not increase in a density-dependent manner. Contrarily, the total activity of AS was extremely high and the specific activity was extremely low as a result of proliferation. Regarding of effect of co-cultures on H(2)O(2)-induced cell death, N-MG co-cultures were less effective, but N-AS co-cultures were more effective in protecting N from the oxidative stress. These results suggest that N-MG co-cultures suppress the Tf-IU and N-AS co-cultures stimulate AS proliferation to protect neuronal cells. Brain cells from aceruloplasminemia with mutations in the ceruloplasmin gene take up iron by Tf-IU. Therefore, the different mechanisms of neuronal cell protection by MG and AS may explain the pathophysiological observations in the brains of patient with aceruloplasminemia.

Dysregulation of iron metabolism in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.

Dysregulation of iron metabolism has been observed in patients with neurodegenerative diseases (NDs). Utilization of several importers and exporters for iron transport in brain cells helps maintain iron homeostasis. Dysregulation of iron homeostasis leads to the production of neurotoxic substances and reactive oxygen species, resulting in iron-induced oxidative stress. In Alzheimer's disease (AD) and Parkinson's disease (PD), circumstantial evidence has shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation. Several genetic studies have revealed mutations in genes associated with increased iron uptake, increased oxidative stress, and an altered inflammatory response in amyotrophic lateral sclerosis (ALS). Here, we review the recent findings on brain iron metabolism in common NDs, such as AD, PD, and ALS. We also summarize the conventional and novel types of iron chelators, which can successfully decrease excess iron accumulation in brain lesions. For example, iron-chelating drugs have neuroprotective effects, preventing neural apoptosis, and activate cellular protective pathways against oxidative stress. Glial cells also protect neurons by secreting antioxidants and antiapoptotic substances. These new findings of experimental and clinical studies may provide a scientific foundation for advances in drug development for NDs.

Supplemental cellular protection by a carotenoid extends lifespan via Ins/IGF-1 signaling in Caenorhabditis elegans.

Astaxanthin (AX), which is produced by some marine animals, is a type of carotenoid that has antioxidative properties. In this study, we initially examined the effects of AX on the aging of a model organism C. elegans that has the conserved intracellular pathways related to mammalian longevity. The continuous treatments with AX (0.1 to 1 mM) from both the prereproductive and young adult stages extended the mean lifespans by about 16-30% in the wild-type and long-lived mutant age-1 of C. elegans. In contrast, the AX-dependent lifespan extension was not observed even in a daf-16 null mutant. Especially, the expression of genes encoding superoxide dismutases and catalases increased in two weeks after hatching, and the DAF-16 protein was translocated to the nucleus in the AX-exposed wild type. These results suggest that AX protects the cell organelle mitochondria and nucleus of the nematode, resulting in a lifespan extension via an Ins/IGF-1 signaling pathway during normal aging, at least in part.

Superoxide anion contributes to the induction of tumor necrosis factor alpha (TNFα) through activation of the MKK3/6-p38 MAPK cascade in rat microglia.

Stimulation of rat microglia with lipopolysaccharide (LPS) in vitro induces production of the inflammatory/cytotoxic cytokine tumor necrosis factor alpha (TNFα) along with superoxide anion (O(2)(-)) and nitric oxide (NO). In this study, we investigated the role of O(2)(-) and NO in the induction of TNFα in microglia. The LPS-inducible TNFα was significantly suppressed by pretreatment with the O(2)(-) scavenger N-acetyl cysteine (NAC), but not by the NO scavenger 2-(4-Carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide, suggesting the close association of O(2)(-) with TNFα induction. NAC strongly depressed phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), which is necessary for inducing TNFα in microglia. On the other hand, an O(2)(-) donor, 3-(4-Morpholinyl)sydnonimine (SIN-1), induced TNFα in microglia, and the effects of SIN-1 were completely abolished in the presence of superoxide dismutase. There is little likelihood that the NO produced in SIN-1 degradation induces TNFα in microglia, because TNFα was not induced in microglia exposed to the NO-donor S-nitroso-N-acetyl-dl-penicillamine. Moreover, the addition of SIN-1 to microglia resulted in activation of p38 MAPK and its upstream kinase MKK3/6. Taken together, these results showed that O(2)(-) is an important signaling molecule for activating the MKK3/6-p38 cascade, which is requisite for inducing TNFα in microglia.

Modulation of iron regulatory protein-1 by various metals.

Iron regulatory protein-1 (IRP-1) is known as a cytosolic aconitase and a central regulator of iron (Fe) homeostasis. IRP-1 regulates the expression of Fe metabolism-related proteins by interacting with the Fe-responsive element (IRE) in the untranslated regions of mRNAs of these proteins. However, it is less known whether IRP-1 modulates various non-Fe metals. In the present study, we showed that treatment of homogenously purified IRP-1 with non-Fe metals decreased the affinity to IRE in RNA band shift assays and increased aconitase activity. Non-Fe metals also inhibited (55)Fe incorporation into the fourth labile position of the Fe-S cluster of IRP-1. In PLC hepatoma cells, metal loading inactivated binding activity and activated enzyme activity. It also suppressed transferrin receptor mRNA expression in the cells. These results suggest that various non-Fe metals modulate IRP-1 by conversion of the 3Fe-4S apo-form to a [1 non-Fe metal + 3Fe]-4Fe holo-form.