Cognitive dysfunction and amyloid β accumulation are ameliorated by the ingestion of green soybean extract in aged mice

AbstractThe effects of soybean extracts were investigated in senescence-accelerated (SAMP10) mice, a mouse model of brain senescence with cognitive dysfunction. Mature soybeans are usually yellow. However, the green soybean retains green color after being ripened. Cognitive functions were significantly better-preserved in aged mice fed green soybean than age-matched control mice with or without yellow soybean feeding. Molecular mechanisms of the beneficial effect of green soybean on brain functions were examined through transcriptome analysis of SAMP10 hippocampus. The high expression of Ptgds was significantly associated with green soybean diet, which encodes lipocalin-type prostaglandin D2 synthase, a putative endogenous amyloid β(Αβ)-chaperone. In consonance, Aplp1 expression was significantly reduced, a member of amyloid precursor proteins. Furthermore, the amount of Aβ 40 and 42 was reduced in the insoluble fraction of cerebral cortex. These results suggest that the intake of green soybean ameliorates cognitive dysfunction of aged mice through the reduction of Aβ accumulation

Effects of various phytochemicals on indoleamine 2,3-dioxygenase 1 activity: galanal is a novel, competitive inhibitor of the enzyme.

Indoleamine 2,3-dioxygenase (IDO) 1, that catalyzes the first and rate-limiting step in the degradation of L-tryptophan, has an important immunomodulatory function. The activity of IDO1 increases in various inflammatory diseases, including tumors, autoimmune diseases, and different kinds of inflammation. We evaluated the suppressive effect of plant extracts or phytochemicals on IDO1 induction and activity; sixteen kinds of plants extracts and fourteen kinds of phytochemicals were examined. As a result, the methanol extracts of Myoga flower buds, which are traditional Japanese foods, and labdane-type diterpene galanal derived from Myoga flowers significantly suppressed IDO1 activity. The Lineweaver-Burk plot analysis indicated that galanal is a competitive inhibitor. Galanal attenuated L-kynurenine formation with an IC₅₀ value of 7.7 µM in the assay system using recombinant human IDO1, and an IC₅₀ value of 45 nM in the cell-based assay. Further, mechanistic analysis revealed that galanal interfered with the transcriptional function of the nuclear factor-κB and the interferon-γ signaling pathway. These effects of galanal are important for immune response. Because the inhibitory effect of galanal on IDO1 activity was stronger than that of 1-methyl tryptophan, a tryptophan analog, galanal may have great potential as the novel drug for various immune-related diseases

Inhibition by galanal of the IFN-γ dependent pathway.

<p>(A) L-Kyn formation in IFN-γ (100U)-treated THP-1 cells with and without various concentrations (1-5 µM) of galanal. L-Kyn formed after 24-hr incubation was measured by HPLC. Data are the mean ± SD. ***P<0.001. (B) Expression of IDO1 mRNA in IFN-γ (100 U)-treated THP-1 cells with and without galanal (1-5 µM) after 24-hr incubation. IDO1 mRNA expressed in IFN-γ -treated THP-1 cells with and without galanal was measured using RT-PCR. (C) The phosphorylation of stat1 in IFN-γ (100 U)-treated THP-1 cells with and without galanal after 15-min or 30-min incubation. n. Data are the mean ± SD. ***P<0.001.</p

Effects of plant extracts and phytochemicals on IDO1 induction.

<p>(A) The expression of IDO1 mRNA in LPS-stimulated THP-1 cells with and without either plant extracts or phytochemicals. THP-1 cells were incubated with LPS (50 ng/ml) and either plant extracts (30 µg/ml each) or phytochemicals (10 µM each). The levels of IDO1 mRNA were measured using RT-PCR. (B) L-Kyn formation from L-Trp in LPS-stimulated THP-1 cells with and without either plant extracts or phytochemicals. L-Kyn formed in the LPS-stimulated cells with each treatment after 24-hr incubation was measured by HPLC. (C) HEK293cells transfected with human IDO1 were incubated with galanal, curcumin, andrographolide, quercetin, or luteolin (5 µM each). The concentration of L-Kyn formed after 48-hr incubation was measured by HPLC. Data are expressed as the mean ± SD (n = 3). ***P<0.001. **P<0.01.</p

Effect of galanal on IDO1 activity in different cell species.

<p>HEK 293 cells transfected with human IDO1 (A) or mouse IDO1 (B) were treated with various concentrations (1-5 µM) of galanal for 48 hrs. Data are mean ± SD (n = 3). **P<0.01.</p

Inhibition by galanal of the NFκ-B signal transduction pathway.

<p>(A) L-Kyn formation in LPS (50 ng/ml)-treated THP-1 cells with and without various concentrations (1-5 µM) of galanal. L-Kyn formed after 24-hr incubation was measured by HPLC. Data are the mean ± SD. ***P<0.001. (B) Expression of IDO1 mRNA in LPS-treated THP-1 cells with and without galanal after 24 hrs incubation. The mRNA expressed was measured using RT-PCR. (C) Cytoplasmic expression of IDO1 and Iκ-Bα proteins in LPS (50 ng/ml)-treated THP-1 cells with and without galanal after 24 hrs incubation. (D) The phosphorylation of IKK-α, IκB-α, and NFκ-B in LPS (50 ng/ml)-treated THP-1 cells with and without galanal after 60-min incubation. Data are the mean ± SD. ***P<0.001.</p

Kinetic analysis for enzymatic IDO1 inhibition by galanal and IC₅₀ value of galanal.

<p>The mode of enzymatic IDO1 inhibition by galanal. The mode of the inhibition was analyzed using the (A) Michaelis-Menten model, or (B) the Lineweaver-Burk plot in the presence or absence of galanal. (C) The IC₅₀ value of galanal for the enzymatic activity of IDO1.</p

Inhibition of cellular IDO1 activity by galanal.

<p>LPS-stimulated THP-1 cells were exposed to various concentrations of galanal. Percentage inhibition in LPS-stimulated THP-1 cells against control cells was plotted and IC₅₀ value determined.</p