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.

Influx and Efflux Transporters Contribute to the Increased Dermal Exposure to Active Metabolite of Regorafenib After Repeated Oral Administration in Mice.

The multikinase inhibitor regorafenib, which is a standard treatment for certain cancer patients after disease progression following other approved therapies, exhibits delayed-onset dermal toxicity. Here, we aimed to clarify the mechanisms that contribute to the increased dermal exposure to active metabolite M-5 of regorafenib after repeated oral administration. The dermal concentration of M-5 at 24 h after the last 5 oral administrations of regorafenib in mdr1a/1b/bcrp-/- mice was more than 190 times that in wild-type mice. The skin-to-plasma concentration ratio of M-5 in mdr1a/1b/bcrp-/- was also higher than in wild-type mice, suggesting possible involvement of P-glycoprotein and breast cancer resistance protein in regulating the dermal distribution. The area under the plasma concentration-time curve values of M-5 and its precursor M-2 in plasma of mdr1a/1b/bcrp-/- were at most 26 and 3 times those in wild-type mice, respectively. Interestingly, repeated administration of regorafenib markedly increased the area under the plasma concentration-time curve of M-5 in plasma, but not liver, compared with a single dose. Intravenous administration of M-5 dose-dependently reduced the liver-to-plasma concentration ratio. Our results indicate that hepatic uptake of M-5 may partially explain the accumulation of M-5 in the systemic circulation, but multiple factors, including influx and efflux transporters, are involved in determining dermal exposure to M-5.

Combination Metabolomics Approach for Identifying Endogenous Substrates of Carnitine/Organic Cation Transporter OCTN1.

PURPOSE: Solute carrier SLC22A4 encodes the carnitine/organic cation transporter OCTN1 and is associated with inflammatory bowel disease, although little is known about how this gene is linked to pathogenesis. The aim of the present study was to identify endogenous substrates that are associated with gastrointestinal inflammation. METHODS: HEK293/OCTN1 and mock cells were incubated with colon extracts isolated from dextran sodium sulfate-induced colitis mice; the subsequent cell lysates were mixed with the amino group selective reagent 3-aminopyridyl-N-hydroxysuccinimidyl carbamate (APDS), to selectively label OCTN1 substrates. Precursor ion scanning against the fragment ion of APDS was then used to identify candidate OCTN1 substrates. RESULTS: Over 10,000 peaks were detected by precursor ion scanning; m/z 342 had a higher signal in HEK293/OCTN1 compared to mock cells. This peak was detected as a divalent ion that contained four APDS-derived fragments and was identified as spermine. Spermine concentration in peripheral blood mononuclear cells from octn1 gene knockout mice (octn1-/-) was significantly lower than in wild-type mice. Lipopolysaccharide-induced gene expression of inflammatory cytokines in peritoneal macrophages from octn1-/- mice was lower than in wild-type mice. CONCLUSIONS: The combination metabolomics approach can provide a novel tool to identify endogenous substrates of OCTN1.