Serotonin (5-hydroxytryptamine; 5-HT) is abundantly present throughout the gastrointestinal tract and stored mostly in enterochromaffin (EC) cells, which are located on the mucosal surface. 5-HT released from EC cells stimulate both intrinsic and extrinsic nerves, which results in various physiological and pathophysiological responses, such as gastrointestinal contractions. EC cells are believed to have the ability to respond to the chemical composition of the luminal contents of the gut; however, the underlying molecular and cellular mechanisms have not been identified. Here, we demonstrate that the transient receptor potential (TRP) cation channel TRPA1, which is activated by pungent compounds or cold temperature, is highly expressed in EC cells. We also found that TRPA1 agonists, including allyl isothiocyanate and cinnamaldehyde, stimulate EC cell functions, such as increasing intracellular Ca 2؉ levels and 5-HT release, by using highly concentrated EC cell fractions and a model of EC cell function, the RIN14B cell line. Furthermore, we showed that allyl isothiocyanate promotes the contraction of isolated guinea pig ileum via the 5-HT 3 receptor. Taken together, our results indicate that TRPA1 acts as a sensor molecule for EC cells and may regulate gastrointestinal function.gastrointestinal tract ͉ RIN14B T he gastrointestinal tract has many functions, such as secretion, motility, and absorption. These functions are affected by various signals from the luminal contents, including nutrient and non-nutrient chemicals, mechanical factors, and microorganisms (1). The endocrine cells of the gut (hereafter enteroendocrine cells) are thought to be highly specialized mucosal cell subpopulations that receive luminal signals. There are more than 10 different types of enteroendocrine cells, and each type produces distinct transmitters/hormones (2). Serotonin (5-HT)-containing enterochromaffin (EC) cells, which are located throughout the gut, are considered to be the most prevalent enteroendocrine cells (3, 4). The 5-HT released from EC cells activate the submucosal sensory branch of the enteric nervous system and also control gastrointestinal motility and chloride secretion via interneurons and motor neurons (5, 6). Hence, EC cells are considered to be a major component of both the physiology and pathophysiology of gastrointestinal function (7,8). It has been suggested that EC cells respond to the contents of the lumen through the activation of receptor-operated or voltage-dependent Ca 2ϩ channels (9), however, the details of the cellular and molecular mechanisms have not yet been clarified.Many ion channels, like the transient receptor potential (TRP) channels expressed in sensory neurons, respond to natural compounds, especially spices and herbal medicines. For example, the vanilloid receptor (TRPV1) responds to the plant component capsaicin (the pungent ingredient in chili peppers), which produces the psychophysical sensation of heat or burning, whereas TRPM8 responds to menthol (found in peppermint), which produces ...

To find a novel human ion channel gene we have executed an extensive search by using a human genome draft sequencing data base. Here we report a novel twopore domain K ؉ channel, TRESK (TWIK-related spinal cord K ؉ channel). TRESK is coded by 385 amino acids and shows low homology (19%) with previously characterized two-pore domain K ؉ channels. However, the most similar channel is TREK-2 (two-pore domain K ؉ channel), and TRESK also has two pore-forming domains and four transmembrane domains that are evolutionarily conserved in the two-pore domain K ؉ channel family. Moreover, we confirmed that TRESK is expressed in the spinal cord. Electrophysiological analysis demonstrated that TRESK induced outward rectification and functioned as a background K ؉ channel. Pharmacological analysis showed TRESK to be inhibited by previously reported K ؉ channel inhibitors Ba 2؉ , propafenone, glyburide, lidocaine, quinine, quinidine, and triethanolamine. Functional analysis demonstrated TRESK to be inhibited by unsaturated free fatty acids such as arachidonic acid and docosahexaenoic acid. TRESK is also sensitive to extreme changes in extracellular and intracellular pH. These results indicate that TRESK is a novel two-pore domain K ؉ channel that may set the resting membrane potential of cells in the spinal cord.

Hepatocellular carcinoma is an aggressive cancer with poor prognosis. Fibroblast growth factor 19, a member of the fibroblast growth factor family, is a ligand for fibroblast growth factor receptor 4. Moreover, it plays a crucial role in the progression of hepatocellular carcinoma. ASP5878 is a novel inhibitor of fibroblast growth factor receptors 1, 2, 3, and 4 that is under development. It inhibits fibroblast growth factor receptor 4 kinase activity with an IC 50 of 3.5 nmol/L. ASP5878 potently suppressed the growth of the fibroblast growth factor 19-expressing hepatocellular carcinoma cell lines Hep3B2

A series of 5,7-disubstituted 1-cyclopropyl-6,8-difluoro-4(1H)-oxoquinoline-3-carboxylic acids (10-36) were prepared; the C-5 substituent in these compounds comprised halo, hydroxy, mercapto, and amino groups and the C-7 functional group included variously substituted piperazines. In vitro antibacterial screening results indicated that the amino group was optimal among the C-5 substituents. A combination of the C-5 amino group and the C-7 3,5-dimethylpiperazinyl appendage in this series conferred the best overall antibacterial property with lack of adverse drug interactions. Compound 36k [named sparfloxacin, originally AT-4140, 5-amino-1-cyclopropyl-6,8-difluoro-7-(cis-3,5-dimethyl-1-piperazinyl)- 4(1H)-oxoquinoline-3-carboxylic acid] was superior to ciprofloxacin in both in vitro and in vivo potency and hence was selected as a promising candidate for an improved therapeutic agent.

The title compounds (28-56) with an amino- and/or hydroxy-substituted cyclic amino group at C-7 were prepared with 1-substituted 7-chloro-, 7-(ethylsulfonyl)-, and 7-(tosyloxy)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- carboxylic acids and their ethyl esters (3-7) with cyclic amines such as 3-aminopyrrolidine. The N-1 substituent includes ethyl, vinyl, and 2-fluoroethyl groups. As a result of in vitro and in vivo antibacterial screenings, three compounds, 1-ethyl- and 1-vinyl-7-(3-amino-1-pyrrolidinyl)-6-fluoro- 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids (33a and 33b) and 1-vinyl-7-[3-(methylamino)-1-pyrrolidinyl] analogue 34b, were found to be more active than enoxacin (2) and to be worthy of further biological study. Structure-activity relationships are discussed.