Suppression of colonic oxidative stress caused by chronic ethanol administration and attenuation of ethanol-induced colitis and gut leakiness by oral administration of sesaminol in mice.

Chronic consumption of excess ethanol is one of the major risk factors for colorectal cancer (CRC), and the pathogenesis of ethanol-related CRC (ER-CRC) involves ethanol-induced oxidative-stress and inflammation in the colon and rectum, as well as gut leakiness. In this study, we hypothesised that oral administration of sesaminol, a sesame lignan, lowers the risk of ER-CRC because we found that it is a strong antioxidant with very low prooxidant activity. This hypothesis was examined using a mouse model, in which 2.0% v/v ethanol was administered ad libitum for 2 weeks with or without oral gavage with sesaminol (2.5 mg per day). Oral sesaminol administration suppressed the ethanol-induced colonic lesions and the ethanol-induced elevation of the colonic levels of oxidative stress markers (8-hydroxy-2'-deoxyguanosine, malondialdehyde, and 4-hydroxyalkenals). It consistently suppressed the chronic ethanol-induced expressions of cytochrome P450-2E1 and inducible nitric oxide synthase and upregulated heme oxygenase-1 expression, probably via the nuclear factor erythroid-derived 2-like 2 pathway in the mouse colon. Oral sesaminol administration also suppressed the chronic ethanol-induced elevation of colonic inflammation marker levels, such as those of tumour necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, probably via the nuclear factor-kappa B pathway. Moreover, it prevented the chronic ethanol-induced gut leakiness by restoring tight junction proteins, giving rise to lower plasma endotoxin levels compared with those of ethanol-administered mice. All of these results suggest that dietary supplementation of sesaminol may lower the risk of ER-CRC by suppressing each of the above-mentioned steps in ER-CRC pathogenesis.

Sesaminol prevents Parkinson's disease by activating the Nrf2-ARE signaling pathway.

Parkinson's disease (PD) is a neurodegenerative disease caused by the degeneration of substantia nigra neurons due to oxidative stress. Sesaminol has strong antioxidant and anti-cancer effects. We investigated the preventive effect on PD as a new physiological action of sesaminol produced from sesaminol glycoside using in vitro and in vivo PD models. To prepare an in vitro PD model, 6-hydroxydopamine (6-OHDA) was added to human neuroblastoma (SH-SY5Y cells). The viability of SH-SY5Y cells decreased dose-dependently following 6-OHDA treatment, but the addition of sesaminol restored viability to the control level. 6-OHDA increased intracellular reactive oxygen species production, and the addition of sesaminol significantly suppressed this increase. No Nrf2 expression in the nucleus was observed in the control group, but a slight increase was observed in the 6-OHDA group. The sesaminol group showed strong expression of Nrf2 in the cytoplasm and nucleus. NAD(P)H: quinone oxidoreductase (NQO1) activity was enhanced in the 6-OHDA group and further enhanced in the sesaminol group. Furthermore, the neurotoxine rotenone was orally administrated to mice to prepare an in vivo PD model. The motor function of rotenone-treated mice was shorter than that of the control group, but a small amount of sesaminol restored it to the control level. The intestinal motility in the rotenone group was significantly lower than that in the control group, but it remained at the control level in the sesaminol group. The expression of α-synuclein in the substantia nigra increased in the rotenone group but decreased in the sesaminol group. The rotenone group exhibited shortening and damage to the colonic mucosa, but these abnormalities of the colonic mucosa were scarcely observed in the sesaminol group. These results suggest that sesaminol has a preventative effect on PD.

Purification, gene cloning, and biochemical characterization of a ß-glucosidase capable of hydrolyzing sesaminol triglucoside from Paenibacillus sp. KB0549.

The triglucoside of sesaminol, i.e., 2,6-O-di(ß-D-glucopyranosyl)-ß-D- glucopyranosylsesaminol (STG), occurs abundantly in sesame seeds and sesame oil cake and serves as an inexpensive source for the industrial production of sesaminol, an anti-oxidant that displays a number of bioactivities beneficial to human health. However, STG has been shown to be highly resistant to the action of ß-glucosidases, in part due to its branched-chain glycon structure, and these circumstances hampered the efficient utilization of STG. We found that a strain (KB0549) of the genus Paenibacillus produced a novel enzyme capable of efficiently hydrolyzing STG. This enzyme, termed PSTG, was a tetrameric protein consisting of identical subunits with an approximate molecular mass of 80 kDa. The PSTG gene was cloned on the basis of the partial amino acid sequences of the purified enzyme. Sequence comparison showed that the enzyme belonged to the glycoside hydrolase family 3, with significant similarities to the Paenibacillus glucocerebrosidase (63% identity) and to Bgl3B of Thermotoga neapolitana (37% identity). The recombinant enzyme (rPSTG) was highly specific for ß-glucosidic linkage, and k cat and k cat/K m values for the rPSTG-catalyzed hydrolysis of p-nitrophenyl-ß-glucopyraniside at 37°C and pH 6.5 were 44 s(-1) and 426 s(-1) mM(-1), respectively. The specificity analyses also revealed that the enzyme acted more efficiently on sophorose than on cellobiose and gentiobiose. Thus, rPSTG is the first example of a ß-glucosidase with higher reactivity for ß-1,2-glucosidic linkage than for ß-1,4- and ß-1,6-glucosidic linkages, as far as could be ascertained. This unique specificity is, at least in part, responsible for the enzyme's ability to efficiently decompose STG.