Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.2152/jmi.67.174.

Language：English   Publishing type：Research paper (scientific journal)  

The influence of a caregiver's stress on the development of childhood asthma is an important aspect of the treatment and prevention of illness. Many cross-sectional studies have investigated the association between parenting attitude and/or caregiver's stress and childhood asthma morbidity, but prospective studies are more advantageous than cross-sectional studies in interpreting a causal relationship from the results. We here present an overview of prospective studies that have reported a relationship between parental stress and the morbidity or course of childhood asthma and discuss the role of parental mental health in its prevention and treatment. Almost all of the studies referred to in this paper show that caregiver (mostly mothers) stress contributed to the onset and to a poor prognosis, while only a few studies have examined the adverse effect of paternal stress on childhood asthma. Their results are inconsistent, and there is insufficient data examining specific stress-related properties that can be targeted in intervention studies. Not only maternal but also paternal influence should be considered in future studies, and it will be important to assess specific stress-related properties that can be the foundation of specific intervention methods.

DOI： 10.1186/s13030-015-0034-4. eCollection 2015.

Language：English   Publishing type：Research paper (scientific journal)  

Activation of the non-phagocytic superoxide-producing NADPH oxidase Nox1, complexed with p22(phox) at the membrane, requires its regulatory soluble proteins Noxo1 and Noxa1. However, the role of the small GTPase Rac remained to be clarified. Here we show that Rac directly participates in Nox1 activation via interacting with Noxa1. Electropermeabilized HeLa cells, ectopically expressing Nox1, Noxo1, and Noxa1, produce superoxide in a GTP-dependent manner, which is abrogated by expression of a mutant Noxa1(R103E), defective in Rac binding. Superoxide production in Nox1-expressing HeLa and Caco-2 cells is decreased by depletion or sequestration of Rac; on the other hand, it is enhanced by expression of the constitutively active Rac1(Q61L), but not by that of a mutant Rac1 with the A27K substitution, deficient in binding to Noxa1. We also demonstrate that Nox1 activation requires membrane recruitment of Noxa1, which is normally mediated via Noxa1 binding to Noxo1, a protein tethered to the Nox1 partner p22phox: the Noxa1-Noxo1 and Noxo1-p22phox interactions are both essential for Nox1 activity. Rac likely facilitates the membrane localization of Noxa1: although Noxa1(W436R), defective in Noxo1 binding, neither associates with the membrane nor activates Nox1, the effects of the W436R substitution are restored by expression of Rac1( Q61L). The Rac-Noxa1 interaction also serves at a step different from the Noxa1 localization, because the binding-defective Noxa1( R103E), albeit targeted to the membrane, does not support superoxide production by Nox1. Furthermore, a mutant Noxa1 carrying the substitution of Ala for Val-205 in the activation domain, which is expected to undergo a conformational change upon Rac binding, fully localizes to the membrane but fails to activate Nox1.

DOI： 10.1074/jbc.M513665200

Language：English   Publishing type：Research paper (scientific journal)  

Nox3, a member of the superoxide-producing NADPH oxidase (Nox) family, participates in otoconia formation in mouse inner ears, which is required for perception of balance and gravity. The activity of other Nox enzymes such as gp91(phox/)Nox2 and Nox1 is known to absolutely require both an organizer protein (p47(phox) or Noxo1) and an activator protein( p67(phox)orNoxa1); for the p47(phox)-dependent activation of these oxidases, treatment of cells with stimulants such as phorbol 12-myristate 13-acetate is also indispensable. Here we show that ectopic expression of Nox3 in various types of cells leads to phorbol 12-myristate 13-acetate-independent constitutive production of a substantial amount of superoxide under the conditions where gp91(phox) and Nox1 fail to generate superoxide, i.e. in the absence of the oxidase organizers and activators. Nox3 likely forms a functional complex with p22(phox); Nox3 physically interacts with and stabilizes p22(phox), and the Nox3-dependent superoxide production is totally dependent on p22phox. The organizers p47(phox) and Noxo1 are capable of enhancing the superoxide production by Nox3 in the absence of the activators, and the enhancement requires the interaction of the organizers with p22phox, further indicating a link between Nox3 and p22(phox). The p47(phox)-enhanced Nox3 activity is further facilitated by p67(phox) or Noxa1, whereas the activators cancel the Noxo1-induced enhancement. On the other hand, the small GTPase Rac, essential for the gp91(phox) activity, is likely dispensable to the Nox3 system. Thus Nox3 functions together with p22(phox) as an enzyme constitutively producing superoxide, which can be distinctly regulated by combinatorial use of the organizers and activators.

DOI： 10.1074/jbc.M414548200

Language：English   Publishing type：Research paper (scientific journal)  

The phagocyte NADPH oxidase is dormant in resting cells but becomes activated during phagocytosis to produce superoxide, a precursor of microbicidal oxidants, thereby playing a crucial role in host defence. The catalytic core of this enzyme comprises the two membranous subunits gp91(phox)/Nox2 and p22(phox). The oxidase activation requires the small GTPase Rac and the SH3 domain-containing proteins p47(phox) and p67(phox); they normally exist in the cytoplasm and translocate upon cell stimulation to the membrane. The translocation depends on a stimulus-induced conformational change of p47(phox), which leads to the SH3 domain-mediated interaction with p22(phox), a binding required for the gp91(phox)/Nox2-dependent superoxide production. Activation of Nox1, an oxidase that is likely involved in host defence at the colon, requires novel proteins homologous to p47(phox) and p67(phox) designated Noxo1 and Noxa1, respectively. Noxo1 and Noxa1, both expressed abundantly in the colon, are capable of constitutively activating Nox1. The constitutive activation may be due to the property of Noxo1: in contrast with p47(phox), Noxo1 seems to normally associate with p22(phox), which is required for the Nox1 activation. We will also describe the mechanism underlying regulation of the third oxidase Nox3, which exits in fetal kidney and inner ears.

Language：English   Publishing type：Research paper (scientific journal)  

The catalytic core of a superoxide-producing NADPH oxidase (Nox) in phagocytes is gp91(phox)/Nox2, a membrane-integrated protein that forms a heterodimer with p22(phox) to constitute flavocytochrome b(558). The cytochrome becomes activated by interacting with the adaptor proteins p47(phox) and p67(phox) as well as the small GTPase Rac. Here we describe the cloning of human cDNAs for novel proteins homologous to p47(phox) and p67(phox), designated p41(nox) and p51(nox), respectively; the former is encoded by NOXO1 <LF>(Nox organizer 1), and the latter is encoded by NOXA1 (Nox activator 1). The novel homologue p41(nox) interacts with p22(phox) via the two tandem SH3 domains, as does p47(phox). The protein p51(nox) as well as p67(phox) can form a complex with p47(phox) and with p41(nox) via the C-terminal SH3 domain and binds to GTP-bound Rac via the N-terminal domain containing four tetratricopeptide repeat motifs. These bindings seem to play important roles, since p47(phox) and p67(phox) activate the phagocyte oxidase via the same interactions. Indeed, p41(nox) and p51(nox) are capable of replacing the corresponding classical homologue in activation of gp91(phox). Nox1, a homologue of gp91(phox), also can be activated in cells, when it is coexpressed with p41(nox) and p51(nox), with p41(nox) and p67(phox), or with p47(phox) and p51(nox); in the former two cases, Nox1 is partially activated without any stimulants added, suggesting that p41(nox) is normally in an active state. Thus, the novel homologues p41(nox) and p51(nox) likely function together or in combination with a classical one, thereby activating the two Nox family oxidases.

DOI： 10.1074/jbc.M212856200

Event date： 2016.8

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：宮崎県宮崎市   Country：Japan  

Event date： 2007.10

Language：Japanese  

Venue：宮崎   Country：Japan  

Event date： 2007.5

Language：Japanese  

Venue：仙台   Country：Japan