Hiroshi Momota

Protective effect against Parkinson's disease-related insults through the activation of XBP1.

The accumulation of misfolded and unfolded proteins in endoplasmic reticulum (ER) induces ER stress, activating the unfolded protein response (UPR). Recent evidence has suggested the relationship between UPR and dopaminergic neuronal cell death in Parkinsons disease (PD); however, it remains unclear whether it makes sense to modulate UPR, to mitigate the progression of PD. In this study, we investigated a role of the IRE1 alpha-XBP1 pathway in the survival of dopaminergic cells, under stress induced by PD-related insults. The exogenous expression of the active-form XBP1 (XBP1s) protein had protective effects against cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and proteasome inhibitors. Moreover, adenoviral XBP1s expression significantly suppressed the degeneration of dopaminergic neurons in the mouse model of PD, as induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These results demonstrate that the enhancement of XBP1 could be a novel PD therapeutic strategy.

Immunosuppressive constituents from Saussurea medusa.

The methanol extract of Saussurea medusa Maxim afforded two lignans: 2alpha-guaicyl-4-oxo-6alpha-catechyl-3,7-dioxabicyclo [3.3.0]octane and 1alpha-hydroxy-2alpha,4alpha-guaicyl-3,7-dioxabicyclo[3.3.0]octane; two chlorophyll derivatives: 13-epi-phaeophorbide-a and 13-epi-phaeophorbide-a methyl ester; one megastigmane derivative: 3beta-hydroxy-5alpha,6alpha-epoxy-7-megastigmen-9-one, along with 19 known compounds. Their structures were established on the basis of spectroscopic studies.

Immunosuppressive terpenoids from extracts of Tripterygium wilfordii

Abstract The clinically used extract (TΠ) of Tripterygium wilfordii Hook f. give 19 new compounds, including five kaurane diterpenes (1–5), one manoyl oxide diterpene (6), and one abietane diterpene (7), three ursene triterpenes (8, 9 and 15), six oleanane triterpenes (10–13, 16 and 19), and three friedelane triterpenes (14, 17 and 18), as well as 15 known compounds (20–34). Their structures were elucidated by spectroscopy and X-ray analysis. Based on the screening of isolated compounds and other compounds reported in previous papers [J. Nat. Prod. 62 (1999) 1522; J. Nat. Prod. (2001) in press; Phytochemistry 53 (2000) 805], we identified the main components that are responsible for the therapeutic effect of TΠ.

Triterpenoids from Tripterygium wilfordii

The extract (T(II)) of Tripterygium wilfordii Hook f. afforded four triterpenoids: wilforic acid D (3beta,24-epoxy-2alpha-hydroxy-24R*-ethoxy-29-friedelanoic acid); (E) 3beta,24-epoxy-2-oxo-3alpha-hydroxy-29-friedelanoic acid; (F) 2beta-hydroxy-3-oxo-friedelan-29-oic acid; 29-hydroxy-3-oxo-olean-12-en-28-oic acid and 17 known triterpenoids. Their structures were established on the basis of spectroscopic studies. In a bioactivity analysis, only the known dulcioic acid compound showed a significant inhibitory effect on cytokine production.

Identification and Characterization of Cell Lines with a Defect in a Post-adsorption Stage of Sendai Virus-mediated Membrane Fusion

In the early stage of infection, Sendai virus delivers its genome into the cytoplasm by fusing the viral envelope with the cell membrane. Although the adsorption of virus particles to cell surface receptors has been characterized in detail, the ensuing complex process that leads to the fusion between the lipid bilayers remains mostly obscure. In the present study, we identified and characterized cell lines with a defect in the Sendai virus-mediated membrane fusion, using fusion-mediated delivery of fragment A of diphtheria toxin as an index. These cells, persistently infected with the temperature-sensitive variant Sendai virus, had primary viral receptors indistinguishable in number and affinity from those of parental susceptible cells. However, they proved to be thoroughly defective in the Sendai virus-mediated membrane fusion. We also found that viral HN protein expressed in the defective cells was responsible for the interference with membrane fusion. These results suggested the presence of a previously uncharacterized, HN-dependent intermediate stage in the Sendai virus-mediated membrane fusion.

Quantitative trait loci for lipid metabolism in the study of OLETF x (OLETF x Fischer 344) backcross rats.

1. The Otsuka Long‐Evans Tokushima Fatty (OLETF) rat is a model of type II diabetes with accompanying dyslipidaemia and obesity.

Effects of Dmo1 on obesity, dyslipidaemia and hyperglycaemia in the Otsuka Long Evans Tokushima Fatty strain

Whole-genome scans have identified Dmo1 as a major quantitative trait locus (QTL) for obesity and dyslipidaemia in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. We have produced congenic rats for the Dmo1 locus, using marker-assisted speed congenic protocols, enforced by selective removal of other QTL regions (QTL-marker-assisted counterselection), to efficiently transfer chromosomal segments from non-diabetic Fischer 344 (F344) rats into the OLETF background. In the third generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. We conclude that single-allele correction of an impaired genetic pathway can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.

Substitution of Dmo1 with normal alleles results in decreased manifestation of diabetes in OLETF rats.

Aim: Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes in the Otsuka Long Evans Tokushima Fatty (OLETF) rat strain. To evaluate possible metabolic and pathological improvements generated by correction of the Dmo1 genetic pathway, we produced congenic lines, in which both OLETF Dmo1 alleles are replaced by the F344‐derived genome.

A < 1.7 cM interval is responsible for Dmo1 obesity phenotypes in OLETF rats

1. Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes of male Otsuka Long Evans Tokushima Fatty (OLETF) rats.