Hydrolyzed Salmon Milt Extract Enhances Object Recognition and Location Memory Through an Increase in Hippocampal Cytidine Nucleoside Levels in Normal Mice.

Salmon milt extract contains high levels of nucleic acids and has antioxidant potential. Although salmon milt extract is known to improve impaired brain function in animal models with brain disease, its effects on learning and memory ability in healthy subjects is unknown. The purpose of the present study was to clarify the effect of hydrolyzed salmon milt extract (HSME) on object recognition and object location memory under normal conditions. A diet containing 2.5% HSME induced normal mice to devote more time to exploring novel and moved objects than in exploring familiar and unmoved objects, as observed during novel object recognition and spatial recognition tests, respectively. A diet containing 2.5% nucleic acid fraction purified from HSME also induced similar effects, as measured by the same behavioral tests. This suggests that the nucleic acids may be a functional component contributing to the effects of HSME on brain function. Quantitative polymerase chain reaction analysis revealed that gene expression of the markers for brain parenchymal cells, including neural stem cells, astrocytes, oligodendrocytes, and microglia, in the hippocampi of mice on an HSME diet was higher than that in mice on a control diet. Oral administration of HSME increased concentrations of cytosine, cytidine, and deoxycytidine in the hippocampus. Overall, ingestion of HSME may enhance object recognition and object location memory under normal conditions in mice, at least, in part, via the activation of brain parenchymal cells. Our results thus indicate that dietary intake of this easily ingestible food might enhance brain function in healthy individuals.

Dietary DNA Attenuates the Degradation of Elastin Fibers in the Aortic Wall in Nicotine-Administrated Mice.

Abdominal aortic aneurysm (AAA) is a vascular disease characterized by chronic inflammation in the infrarenal aorta. Epidemiologic data have clearly linked tobacco smoking to aneurysm formation and a faster rate of expansion. It suggested that nicotine, one of the main ingredients of tobacco, has been suggested to be associated with AAA development and rupture. In the condition where no established drugs are available; therefore, an effective approach to prevent the vascular damage from nicotine consumption may be the use of dietary functional food factors. However, little is known about the relationship between dietary components and AAA. In this study, we estimated the effect of dietary deoxyribonucleic acid (DNA) on the vascular wall. After habituation for 5 d, the mice were divided into four groups: control diet and distilled water group (C), DNA-Na diet and distilled water group (DNA), control diet and 0.5 mg/mL nicotine solution group (C-Nic), DNA-Na diet, and 0.5 mg/mL nicotine solution group (DNA-Nic). The dietary DNA attenuated the degradation of elastin fibers induced by nicotine administration. The areas stained positive for MMP-2 in the DNA-Nic group were significantly suppressed compared to C-Nic mice. These data suggest that the dietary DNA may prevent the weakening of the aortic wall via inhibition of the MMP-2-dependent pathway. In conclusion, we have revealed the protective effect of dietary DNA on the vascular pathology of nicotine-administrated mice. A nucleic acid-rich diet might be useful for people who consume nicotine via smoking, chewing tobacco, or nicotine patches.

Protective Effects of Hydrolyzed Nucleoproteins from Salmon Milt against Ethanol-Induced Liver Injury in Rats.

Dietary nucleotides play a role in maintaining the immune responses of both animals and humans. Oral administration of nucleic acids from salmon milt have physiological functions in the cellular metabolism, proliferation, differentiation, and apoptosis of human small intestinal epithelial cells. In this study, we examined the effects of DNA-rich nucleic acids prepared from salmon milt (DNSM) on the development of liver fibrosis in an in vivo ethanol-carbon tetrachloride cirrhosis model. Plasma aspartate transaminase and alanine transaminase were significantly less active in the DNSM-treated group than in the ethanol plus carbon tetrachloride (CCl4)-treated group. Collagen accumulation in the liver and hepatic necrosis were observed histologically in ethanol plus CCl4-treated rats; however, DNSM-treatment fully protected rats against ethanol plus CCl4-induced liver fibrosis and necrosis. Furthermore, we examined whether DNSM had a preventive effect against alcohol-induced liver injury by regulating the cytochrome p450 2E1 (CYP2E1)-mediated oxidative stress pathway in an in vivo model. In this model, CYP2E1 activity in ethanol plus CCl4-treated rats increased significantly, but DNSM-treatment suppressed the enzyme's activity and reduced intracellular thiobarbituric acid reactive substances (TBARS) levels. Furthermore, the hepatocytes treated with 100 mM ethanol induced an increase in cell death and were not restored to the control levels when treated with DNSM, suggesting that digestive products of DNSM are effective for the prevention of alcohol-induced liver injury. Deoxyadenosine suppressed the ethanol-induced increase in cell death and increased the activity of alcohol dehydrogenase. These results suggest that DNSM treatment represents a novel tool for the prevention of alcohol-induced liver injury.

Food-derived hydrophilic antioxidant ergothioneine is distributed to the brain and exerts antidepressant effect in mice.

BACKGROUND: Clinically used antidepressants suffer from various side effects. Therefore, we searched for a safe antidepressant with minimal side effects among food ingredients that are distributed to the brain. Here, we focused on ERGO (ergothioneine), which is a hydrophilic antioxidant and contained at high levels in edible golden oyster mushrooms. ERGO is a typical substrate of carnitine/organic cation transporter OCTN1/SLC22A4, which is expressed in the brain and neuronal stem cells, although little is known about its permeation through the BBB (blood-brain barrier) or its neurological activity. METHODS: To clarify the exposure of ERGO to brain and the possible antidepressant-like effect after oral ingestion, ERGO or GOME (golden oyster mushroom extract) which contains 1.2% (w/w) ERGO was mixed with feed and provided to mice for 2 weeks, and then ERGO concentration and antidepressant-like effect were evaluated by LC-MS/MS and FST (forced swimming test) or TST (tail suspension test), respectively. RESULTS: Diet containing ERGO or GOME greatly increased the ERGO concentrations in plasma and brain, and significantly decreased the immobility time in both FST and TST. The required amount of GOME (~37 mg/day) to show the antidepressant-like effect corresponds to at most 8 g/day in humans. In mice receiving GOME-containing diet, doublecortin-positive cells showed a significant increase from the basal level, suggesting promotion of neuronal differentiation. CONCLUSION: Thus, orally ingested ERGO is transported across the BBB into the brain, where it may promote neuronal differentiation and alleviate symptoms of depression at plausibly achieved level of daily ingestion.

Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis.

Xenobiotic transporters play key roles in disposition of certain therapeutic agents, although limited information is available on their roles other than pharmacokinetic issues. Here, suppressive effect of multispecific organic cation transporter OCTN1/SLC22A4 on liver fibrosis was proposed in liver injury models. After injection of hepatotoxins such as dimethylnitrosamine (DMN) or concanavalin A, hepatic fibrosis, and oxidative stress, evaluated in terms of Sirius red and 4-hydroxy-2-nonenal staining, respectively, were more severe in liver of octn1/slc22a4 gene knockout (octn1(-/-)) mice than that in wild-type mice. DMN treatment markedly increased α-smooth muscle actin and F4/80, markers of activated stellate and Kupffer cells, respectively, in liver of octn1(-/-), but had less effect in wild-type mice. Thus, octn1/slc22a4 gene deletion results in more severe hepatic fibrosis, oxidative stress, and inflammation. DMN-treated wild-type mice showed increased Octn1 staining and hepatic concentration of its food-derived antioxidant ergothioneine (ERGO). The upregulated Octn1 was co-localized with α-smooth muscle actin. Functional expression of Octn1 was demonstrated in activated human hepatic stellate cell lines, LI90 and LX-2. Provision of ERGO-rich feed ameliorated DMN-induced liver fibrosis and oxidative stress. Overall, Octn1 is upregulated in activated stellate cells, resulting in increased delivery of its substrate antioxidant ERGO and a protective effect against liver fibrosis.

Nucleoprotamine diet derived from salmon soft roe protects mouse hippocampal neurons from delayed cell death after transient forebrain ischemia.

The nutritional benefits of nucleoprotamine (NP), the main component of fish soft roe, have been rarely addressed. In the present study, the preventive effect of oral supplements of nucleoprotamine and its derivatives, DNA and protamine (PT), extracted from salmon soft roe, on survival rate and hippocampal cell death induced by transient brain ischemia, was evaluated in mice. Artificially formulated nucleoprotamine-free (NF) diet with/without nucleoprotamine, DNA or protamine was fed orally. One week after commencement of respective diets, animals were subjected to transient brain ischemia, which was performed by common carotid artery (CCA) occlusion for 25 (severe) or 15 min (mild). After severe ischemia, the survival rate of the NF group was lower than that in the group fed standard diet or NP. Morphological changes in the hippocampal CA1 region were estimated 48 h after mild ischemia. The NP and PT groups significantly decreased the neuronal damage compared with the NF group. The number of cell death in the DNA group, however, was affected similar to that of the NF group. Our data suggests that the nucleoprotamine content in salmon soft roe could be a useful nutritional resource for the prevention of cell damage caused by ischemia such as those occurring with cerebral and/or heart infarction.