Methylmercury (MeHg) results in cell death through endoplasmic reticulum (ER) stress. Previously, we reported that MeHg induces S-mercuration at cysteine 383 or 386 in protein disulfide isomerase (PDI), and this modification induces the loss of enzymatic activity. Because PDI is a key enzyme for the maturation of nascent protein harboring a disulfide bond, the disruption in PDI function by MeHg results in ER stress via the accumulation of misfolded proteins. However, the effects of MeHg on unfolded protein response (UPR) sensors and their signaling remain unclear. In the present study, we show that UPR is regulated by MeHg. We found that MeHg specifically attenuated inositol-requiring enzyme 1α (IRE1α)-x-box binding protein 1 (XBP1) branch, but not the protein kinase RNA-like endoplasmic reticulum kinase (PERK) and activating transcriptional factor 6 (ATF6) branches. Treatment with GSK2606414, a specific PERK inhibitor, significantly inhibited MeHg-induced cell death. These findings suggest that MeHg exquisitely regulates UPR signaling involved in cell death.

The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they inhibit novel protein synthesis and upregulate ER chaperones, such as protein disulfide isomerase, to remove unfolded proteins. However, when recovery from ER stress is difficult, the UPR pathway is activated to eliminate unhealthy cells. This signaling transition is the key event of many human diseases. However, the precise mechanisms are largely unknown. Intriguingly, reactive electrophilic species (RES), which exist in the environment or are produced through cellular metabolism, have been identified as a key player of this transition. In this review, we focused on the function of representative RES: nitric oxide (NO) as a gaseous RES, 4-hydroxynonenal (HNE) as a lipid RES, and methylmercury (MeHg) as an environmental organic compound RES, to outline the relationship between ER stress and RES. Modulation by RES might be a target for the development of next-generation therapy for ER stress-associated diseases.

Astrocytes are known to regulate normal brain function. Monoamine oxidase B (MAO-B), an enzyme highly expressed in astrocytes, metabolizes dopamine (DA) and induces reactive oxygen species (ROS) production. We have previously reported that β-lactolin, a whey-derived glycine–threonine–tryptophan–tyrosine tetrapeptide, improves memory impairment in mice by regulating the dopaminergic system; however, the effects of β-lactolin on astrocytes remain unclear. Herein, we investigated the effects of β-lactolin on cultured murine astrocytes. First, we measured intracellular ROS production in lipopolysaccharide-stimulated reactive astrocytes treated with or without β-lactolin, and then determined the role of β-lactolin in DA metabolism in astrocytes by measuring MAO-B enzyme activity and the levels of DA, and its metabolites, in DA-pretreated astrocytes. We found that β-lactolin significantly suppressed ROS production in lipopolysaccharide-stimulated reactive astrocytes (p = 2.76 × 10−6), inhibited MAO-B activity (p = 2.65 × 10−2) and increased intracellular DA levels (p = 1.08 × 10−3), suggesting that β-lactolin could inhibit DA metabolism in astrocytes. These results illustrate the novel protective effects of β-lactolin on reactive astrocytes and suggest their involvement in the memory-improving effects of β-lactolin via the dopaminergic system.

This study aimed to investigate the effect of non-alcoholic beer containing matured hop bitter acids on mood states among healthy adults older than 20 years. This study was an open-label longitudinal intervention design in which each participant served as their control. For 3 weeks, we evaluated the effect of non-alcoholic beer containing 35 mg of matured hop bitter acids on mood, sleep quality, and work performance. The data of 97 participants (age range: 23-72 years, median age: 42) were analyzed. After the intervention, we found that matured hop bitter acids significantly improved total mood state, including anxiety, depression, fatigue, and vigor, compared with the baseline. Furthermore, sleep quality and absolute presenteeism were significantly improved after the intervention compared with the baseline. The present exploratory study suggested that 3-week supplementation with matured hop bitter acids improved mood and peripheral symptoms in persons of a wide range of ages.Although further investigation is needed, the findings suggested that non-alcoholic beer in daily life might become a choice for maintaining mood states.