Pharmacokinetics and tissue distribution of orally administrated imidazole dipeptides in carnosine synthase gene knockout mice.

Imidazole dipeptides (ID) are abundant in skeletal muscle and the brain and have various functions, such as antioxidant, pH-buffering, metal-ion chelation. However, the physiological significance of ID has not been fully elucidated. In this study, we orally administered ID to conventional carnosine synthase gene-deficient mice (Carns-KO mice) to investigate the pharmacokinetics. Carnosine or anserine was administered at a dose of 500 mg (∼2 mmol) per kilogram of mouse body weight, and ID contents in the tissues were measured. No ID were detected in untreated Carns-KO mice. In the ID treatment groups, the ID concentrations in the tissues increased in a time-dependent manner in the gastrocnemius muscle, soleus muscle, and cerebrum after ID administration. Our findings suggest that the Carns-KO mice are a valuable animal model for directly evaluating the effects of dietary ID and for elucidating the physiological functions of oral ID administration.

The Steroidal Alkaloid Tomatidine and Tomatidine-Rich Tomato Leaf Extract Suppress the Human Gastric Cancer-Derived 85As2 Cells In Vitro and In Vivo via Modulation of Interferon-Stimulated Genes.

The steroidal alkaloid tomatidine is an aglycone of α-tomatine, which is abundant in tomato leaves and has several biological activities. Tomatidine has been reported to inhibit the growth of cultured cancer cells in vitro, but its anti-cancer activity in vivo and inhibitory effect against gastric cancer cells remain unknown. We investigated the efficacy of tomatidine using human gastric cancer-derived 85As2 cells and its tumor-bearing mouse model and evaluated the effect of tomatidine-rich tomato leaf extract (TRTLE) obtained from tomato leaves. In the tumor-bearing mouse model, tumor growth was significantly inhibited by feeding a diet containing tomatidine and TRTLE for 3 weeks. Tomatidine and TRTLE also inhibited the proliferation of cultured 85As2 cells. Microarray data of gene expression analysis in mouse tumors revealed that the expression levels of mRNAs belonging to the type I interferon signaling pathway were altered in the mice fed the diet containing tomatidine and TRTLE. Moreover, the knockdown of one of the type I interferon-stimulated genes (ISGs), interferon α-inducible protein 27 (IFI27), inhibited the proliferation of cultured 85As2 cells. This study demonstrates that tomatidine and TRTLE inhibit the tumor growth in vivo and the proliferation of human gastric cancer-derived 85As2 cells in vitro, which could be due to the downregulation of ISG expression.

Anserine, HClO-scavenger, protected against cognitive decline in individuals with mild cognitive impairment.

Neuroinflammation has been recognized as a promising target when considering strategies for treating AD. In particular, it has been shown that neutrophils and MPO-mediated neuroinflammatory responses with the production of HClO play a role in the progression of AD. In this study, we aimed to evaluate the effects of anserine, a scavenger of HClO, on the protection of cognitive declines in persons with MCI. Fifty-eight elderly volunteers were screened, and 36 MCI individuals were assigned either to an active arm, who received 500 mg anserine per day, or a placebo arm, for 12-weeks. To assess cognitive function, we performed MMSE at baseline and after the ingestion. The data of the MMSE for 30 subjects who completed the follow-up tests were analyzed. A significant difference was detected in the change score of MMSE between the active arm (1.9 ± 2.0; n = 15) and the placebo arm (0 ± 2.8; n = 15) (p = 0.036). After the correction with the daily intake of anserine, the significance was elevated (p = 0.0176). Our results suggest that anserine protects elderly persons with MCI from cognitive declines by suppressing MPO-mediated neuroinflammatory responses.

Effect of a dipeptide-enriched diet in an adult Drosophila melanogaster laboratory strain.

Here we present free amino acid profiles for Drosophila melanogaster adults. Imidazol dipeptides anserine and carnosine, which are abundant in mammalian muscle tissue, are not present in Drosophila. Dipeptide-enriched food altered the amino acid balance, suggesting that the free amino acid content is nutrition-dependent and probably mediated by dipeptides.

Antioxidant combination inhibits reactive oxygen species mediated damage.

We examined the preventive activity of naturally occurring antioxidants against three reactive oxygen species using a protein degradation assay. The hydroxyl, hypochlorite, and peroxynitrite radicals are typical reactive oxygen species generated in human body. Previously, we found that hydrophobic botanical antioxidants exhibited specific antioxidant activity against hydroxyl radicals, whereas anserine and carnosine mixture, purified from chicken extract and vitamin C, exhibited antioxidant activities against hypochlorite and peroxynitrite radicals respectively. Since ethanol, used as a solvent in the experiments, also showed an antioxidant action against the hydroxyl radical, we re-assessed antioxidant activities using aqueous solutions of botanical antioxidants. Among the seven hydrophobic antioxidants examined, ferulic acid exhibited the strongest antioxidant activity against the hydroxyl radical. An antioxidant preparation of anserine-carnosine mixture, vitamin C, and ferulic acid prevented oxidative stress by reactive oxygen species. Loss of deformability in human erythrocytes and protein degradation caused by reactive oxygen species were completely inhibited.