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Hakusan, Japan

Kawahata I.,Tohoku University | Yoshida M.,Kotaro Pharmaceutical Co. | Sun W.,Tohoku University | Nakajima A.,Tohoku University | And 9 more authors.
Journal of Neural Transmission

cAMP/PKA/ERK/CREB signaling linked to CRE-mediated transcription is crucial for learning and memory. We originally found nobiletin as a natural compound that stimulates this intracellular signaling and exhibits anti-dementia action in animals. Citrus reticulata or C.unshiu peels are employed as "chinpi" and include a small amount of nobiletin. We here provide the first evidence for beneficial pharmacological actions on the cAMP/PKA/ERK/CREB cascade of extracts from nobiletin-rich C.reticulata peels designated as Nchinpi, the nobiletin content of which was 0.83 ± 0.13 % of the dry weight or 16-fold higher than that of standard chinpi extracts. Nchinpi extracts potently facilitated CRE-mediated transcription in cultured hippocampal neurons, whereas the standard chinpi extracts showed no such activity. Also, the Nchinpi extract, but not the standard chinpi extract, stimulated PKA/ERK/CREB signaling. Interestingly, treatment with the Nchinpi extract at the concentration corresponding to approximately 5 μM nobiletin more potently facilitated CRE-mediated transcriptional activity than did 30 μM nobiletin alone. Consistently, sinensetin, tangeretin, 6-demethoxynobiletin, and 6-demethoxytangeretin were also identified as bioactive substances in Nchinpi that facilitated the CRE-mediated transcription. Purified sinensetin enhanced the transcription to a greater degree than nobiletin. Furthermore, samples reconstituted with the four purified compounds and nobiletin in the ratio of each constituent's content in the extract showed activity almost equal to that of the Nchinpi extract to stimulate CRE-mediated transcription. These findings suggest that above four compounds and nobiletin in the Nchinpi extract mainly cooperated to facilitate potently CRE-mediated transcription linked to the upstream cAMP/PKA/ERK/CREB pathway in hippocampal neurons. © 2013 Springer-Verlag Wien. Source

Minami M.,Chubu University | Suzuki M.,Tropical Plants Resources Research Institute | Hosokawa K.,University of Hyogo | Kondo S.,Kotaro Pharmaceutical Co. | And 2 more authors.
Journal of Natural Medicines

Artemisia campestris L. (Compositae) occurs naturally along the coastline of the Ryukyu Islands and has been traditionally used as a folk medicine for the treatment of liver and kidney disorders. The authors obtained specimens from the Ishigaki and Kume Islands of the Ryukyu Islands, Japan, and from the USA. A survey of the literature revealed that the Japanese name for A. campestris is Niitaka-yomogi or Riukiu-yomogi. Two distinct overall plant-form phenotypes were identified: an erect phenotype with long, upright, and straight main axis and assurgent branches; and a prostrate phenotype, having branches that are longer than the main axis and which grow along the ground. Except for the number of ray flowers, most of the flower head characters in the erect phenotypes were significantly larger than those in the prostrate phenotypes. In this experiment, the flower heads contained only small amounts of either capillarisin (<0.01-0.11 of the dry weight, % DW) and 6,7-dimethylesculetin (<0.01-0.30% DW), or none at all. DNA polymorphisms at two sites of the rpl16-rpl14 spacer region (nucleotide position 181-189 and 291-300 from the 5′ end) revealed the existence of four different haplotypes. The number of adenines at nucleotide positions 291-300 appeared to be polymorphic within A. campestris from the Ryukyu Islands. Conversely, geographic differences between specimens from the Ryukyu Islands and USA manifested as a nine-base deletion at nucleotide positions 181-189. From a pharmacognostical context, the use of A. campestris flower heads as a substitute for Artemisiae capillaris Flos is not effective. © The Japanese Society of Pharmacognosy and Springer 2009. Source

Tatewaki N.,Niigata University of Pharmacy and Applied Life Sciences | Yoshida M.,Kotaro Pharmaceutical Co. | Ando H.,Kotaro Pharmaceutical Co. | Kondo S.,Kotaro Pharmaceutical Co. | Sakamaki T.,Niigata University of Pharmacy and Applied Life Sciences
Journal of Pharmacological Sciences

We have previously reported that schisandrin B (SchB) is a specific inhibitor of ATR (ataxia telangiectasia and Rad-3-related) protein kinase. Since SchB consists of a mixture of its diastereomers gomisin N (GN) and γ-schisandrin (γ-Sch), the inhibitory action of SchB might result from a stereospecific interaction between one of the stereoisomers of SchB and ATR. Therefore, we investigated the effect of GN and γ-Sch on UV (UVC at 254 nm)-induced activation of DNA damage checkpoint signaling in A549 cells. UV-induced cell death (25 - 75 J/m2) was amplified by the presence of the diastereomers, especially GN. At the same time, GN, but not γ-Sch, inhibited the phosphorylation of checkpoint proteins such as p53, structural maintenance of chromosomes 1, and checkpoint kinase 1 in UV-irradiated cells. Moreover, GN inhibited the G2/M checkpoint during UV-induced DNA damage. The in vitro kinase activity of immunoaffinity- purified ATR was dose-dependently inhibited by GN (IC50: 7.28 μM) but not by γ-Sch. These results indicate that GN is the active component of SchB and suggest that GN inhibits the DNA damage checkpoint signaling by stereospecifically interacting with ATR. © 2013 The Japanese Pharmacological Society. Source

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