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Aim: Currently, no information regarding the sennosides A and B content is provided on bofutsushosan extract products for ethical use. In this study, sennosides A and B in bofutsushosan extract products from eight different pharmaceutical companies and those in bofutsushosan decoction were quantitatively analyzed. Additionally, since it has been reported that sennoside A is unstable to heat, the relationship between the different decoction times of Rhubarb and the total extracted amounts of sennosides A and B was investigated. Finally, nuclear magnetic resonance (NMR)‐based metabolomics analysis was performed on Rhubarb extracts to evaluate the variability in the quality of Rhubarb. Methods: Solutions of bofutsushosan extract products, bofutsushosan decoction, and Rhubarb decoction were subjected to solid‐phase extraction, and then were analyzed using HPLC. The five Rhubarb extracts prepared from five different lots were subjected to NMR‐based metabolomics analysis. Results: The quantities of sennosides A and B varied among the bofutsushosan extract products, with a maximum interproduct variation of approximately five‐fold. Sennosides A and B were not significantly unstable to heat up to 60 min. The five Rhubarb samples were classified into three independent clusters. Conclusion: It is recommended that the quantities of sennosides A and B in Kampo extract products, including Rhubarb, be described in the package insert. When preparing Rhubarb‐containing Kampo medicines, sennosides A and B decomposition can be ignored for decoction times of up to 60 min. Further studies on the biological activity of secondary metabolites other than sennosides A and B are necessary for Rhubarb quality control. [ABSTRACT FROM AUTHOR]

Prevention and treatment of Alzheimer disease are urgent problems for elderly people in developed countries. We previously reported that nobiletin, a poly-methoxylated flavone from the citrus peel, improved the symptoms in various types of animal models of memory loss and activated the cAMP responsive element (CRE)-dependent transcription in PC12 cells. Nobiletin activated the cAMP/PKA/MEK/Erk/MAPK signaling pathway without using the TrkA signaling activated by nerve growth factor (NGF). Here, we examined the effect of combination of nobiletin and NGF on the CRE-dependent transcription in PC12 cells. Although NGF alone had little effect on the CRE-dependent transcription, NGF markedly enhanced the CRE-dependent transcription induced by nobiletin. The NGF-induced enhancement was neutralized by a TrkA antagonist, K252a. This effect of NGF was effective on the early signaling event elicited by nobiletin. These results suggested that there was crosstalk between NGF and nobiletin signaling in activating the CRE-dependent transcription in PC12 cells. Key words: Alzheimer disease, CRE-dependent transcription, flavone, nerve growth factor, neuron, nobiletin, PC12 cells. La prevention et le traitement de la maladie d'Alzheimer sont des problemes urgents pour les personnes agees des pays developpes. Anterieurement, nous avons rapporte que la nobiletine, une flavone poly-methoxylee que l'on trouve dans la pelure d'agrumes, permet d'attenuer les symptomes dans divers types de modeles de perte de memoire chez l'animal et d'activer la transcription dependante des elements de reponse a l'AMPc (CRE) dans les cellules PC12. En fait, la nobiletine activait la voie de signalisation AMPc/PKA/MEK/Erk/MAPK sans utiliser la signalisation de la TrkA activee par le facteur de croissance neuronal (NGF). Dans les presents travaux, nous avons etudie les effets de l'association de la nobiletine avec le NGF sur la transcription dependante des CRE dans les cellules PC12. Nous avons observe que l'administration du NGF seul avait peu d'effet sur la transcription dependante des CRE, mais qu'elle amplifiait de facon marquee la transcription dependante des CRE induite par la nobiletine. En fait, l'amplification engendree par le NGF etait neutralisee par le K252a, un antagoniste de la TrkA. En definitive, le NGF agissait des le debut du processus de signalisation engendre par la nobiletine. Ces resultats donnent a penser qu'il y aurait un couplage entre le NGF et la signalisation par la nobiletine pour l'activation de la transcription dependante des CRE dans les cellules PC12. [Traduit par la Redaction] Mots-cles: maladie d'Alzheimer, transcription dependante des CRE, flavone, facteur de croissance neuronal, neurone, nobiletine, cellules PC12., Introduction Alzheimer disease (AD) is a neurodegenerative disorder characterized by impaired cognition and memory loss. The progression of AD takes more than 10 years and the illness results in a [...]

Neprilysin (NEP) is one of the candidate amyloid β protein (Aβ) degrading enzymes affecting brain Aβ clearance. This enzyme declines in the brain with age, which leads to the increased Aβ deposition in Alzheimer's disease (AD). Pharmacological activation of NEP during the aging process, therefore, represents a potential strategy to prevent the development of AD. To examine the influence of nobiletin on neprilysin activity, we measured cellular NEP activity in SK-N-SH cells. Moreover, NEP expression was examined by using reverse transcription--polymerase chain reaction and Western blotting. Measurement of cellular NEP activity showed that nobiletin stimulated this in a dose- and time-dependent manner in SK-N-SH cells. Moreover, nobiletin increased the expression of NEP mRNA, and then the levels of NEP protein, also in a dose- and time-dependent manner. Our findings showed that nobiletin promoted NEP gene and protein expression, resulting in enhancement of cellular NEP activity in SK-N-SH cells. This compound could be a novel AS -degrading compound for use in the development of diseasemodifying drugs to prevent and (or) cure AD. Key words: Alzheimer's disease, dementia, amyloid fS protein, neprilysin, nobiletin, Citrus depressa, SK-N-SH cells. La neprilysine (NEP) est une des enzymes candidates degradant la proteine β amyloide (Aβ) qui affectent la clairance cerebrale d'Aβ. Cette enzyme decline dans le cerveau au cours du vieillissement, et cela conduit a une augmentation du depot d'AS dans la maladie d'Alzheimer (MA). L'activation pharmacologique de NEP durant le vieillissement represente en consequence une strategie potentielle de prevention du developpement de la MA. Afin d'examiner l'influence de la nobiletine, nous avons mesure l'activite cellulaire de la NEP chez les cellules SH-N-SH. De plus, l'expression de la NEP a ete mesuree par RT-PCR et par buvardage Western. La mesure de l'activite cellulaire de la NEP montrait que la nobiletine accroissait cette activite en fonction de la concentration et du temps chez les SK-N-SH. En outre, la nobiletine accroissait l'expression de l'ARNm de la NEP et les niveaux de NEP en fonction de la concentration et du temps. Nos donnees ont montre que la nobiletine favorise l'expression genique de la NEP et l'expression de la proteine, resultant en une augmentation de l'activite cellulaire de la NEP dans les cellules SK-N-SH. Ce compose pourrait devenir un nouveau compose tete de serie capable de degrader l'AfS, en vue de developper des medicaments agissant sur la maladie afin de prevenir et (ou) guerir la MA. [Traduit par la Redaction] Mots-cles: maladie d'Alzheimer, demence, proteine amyloide β, neprilysine, nobiletine, Citrus depressa, cellules SK-N- SH., Introduction Alzheimer's disease (AD) is the most representative cause of dementia, characterized by memory deficit and cognitive decline accompanied by behavioral disorder in old age. One of the characteristic pathological [...]

Three novel steroidal glycosides (1–3) and a previously described steroidal alkaloid glycoside (4) have been isolated from the bulbs of Fritillaria camtschatcensis (L.) Ker Gawl. (Liliaceae). The structures of novel compounds 1–3 were characterized based on NMR spectroscopy and chemical transformations. Compounds 1–3 are furospirostanol glycosides bearing a (3S)-3-hydroxy-3-methylglutaryl moiety at C-26 in the aglycone. Compounds 1–4 were evaluated in terms of their cytotoxic activities toward HL-60 human promyelocytic leukemia cells, A549 human lung adenocarcinoma cells, and SBC-3 human lung small cell carcinoma cells. Only 4 showed moderate cytotoxicity against HL-60, A549, and SBC-3 cells with IC50 values of 22.9, 13.3, and 11.9 µM, respectively. Compound 4 was found to cause necrotic-like cell death in HL-60 cells. [ABSTRACT FROM AUTHOR]