川原 正博

Reducing deaths and diseases due to air pollution is a global challenge enshrined in the Sustainable Development Goals. Currently, there is an urgent need to discover factors that protect the lungs and bronchi, which are the first to be injured and undergo oxidative stress when air pollutants enter the body, and to establish methods to prevent their onset and progression. Metallothionein, a protein present in humans that exerts detoxification and antioxidant effects on toxic metals, has long been known to exert protective effects against liver and kidney diseases. However, no functional analysis of the effects of metallothionein on acute lung injury caused by air pollutants has been reported. Thus, we studied the effect of metallothionein on urban aerosol-dependent acute lung injury using metallothionein knockout (MT-KO) mice and a metallothionein inducer. Most importantly, we found that urban aerosol-dependent acute lung injury was exacerbated in MT-KO mice compared to wild-type (WT) mice. In addition, inflammatory responses and reactive oxygen species production in the lungs were enhanced in MT-KO mice compared to WT mice. Furthermore, we found that the intraperitoneal administration of zinc acetate exerted an antioxidant effect via the induction of metallothionein providing a protective effect against the development of urban aerosol-dependent acute lung injury. These results suggest that the metallothionein protein itself or compounds with metallothionein-inducing action may help prevent acute lung injury caused by air pollutants.

Zinc (Zn) and copper (Cu) are essential for normal brain functions. In particular, Zn and Cu are released to synaptic clefts during neuronal excitation. Synaptic Zn and Cu regulate neuronal excitability, maintain calcium (Ca) homeostasis, and play central roles in memory formation. However, in pathological conditions such as transient global ischemia, excess Zn is secreted to synaptic clefts, which causes neuronal death and can eventually trigger the pathogenesis of a vascular type of senile dementia. We have previously investigated the characteristics of Zn-induced neurotoxicity and have demonstrated that low concentrations of Cu can exacerbate Zn neurotoxicity. Furthermore, during our pharmacological approaches to clarify the molecular pathways of Cu-enhanced Zn-induced neurotoxicity, we have revealed the involvement of Ca homeostasis disruption. In the present review, we discuss the roles of Zn and Cu in the synapse, as well as the crosstalk between Zn, Cu, and Ca, which our study along with other recent studies suggest may underlie the pathogenesis of vascular-type senile dementia.

Neuronal cell death is a key mechanism involved in the development and exacerbation of Parkinson's disease (PD). The excessive production of reactive oxygen species (ROS) is a major cause leading to neuronal death; therefore, compounds that prevent oxidative stress-dependent neuronal death may be promising as a preventive method for PD. Ergothioneine is a natural amino acid with antioxidant properties, and its protective functions in the body are attracting attention. However, there has been no investigation into the protective functions of ergothioneine using in vivo and in vitro PD models. Thus, in this study, we analyzed the efficacy of ergothioneine against 6-hydroxydopamine (6-OHDA)-dependent neuronal cell death using immortalized hypothalamic neurons (GT1-7 cells). First, we found that ergothioneine prevents 6-OHDA-dependent neuronal cell death by suppressing ROS overproduction in GT1-7 cells. The cytoprotective effect of ergothioneine was partially abolished by verapamil, an inhibitor of OCTN1, which is involved in ergothioneine uptake. Furthermore, ergothioneine-rich Rice-koji (Ergo-koji) showed cytoprotective and antioxidant effects similar to those of ergothioneine. Taken together, these results suggest that ergothioneine or foods containing ergothioneine may be an effective method for preventing the development and progression of PD.